Synthesis of nucleoside analogues using acyclic diastereoselective reactions

Article abstract of DOI:10.24820/ark.5550190.p010.832

The design of novel xylo-like nucleoside analogues bearing a C3’ all-carbon quaternary center and a C2’-hydroxy substituent is described. Synthesis of this scaffold makes use of highly diastereoselective transformations on acyclic substrates. Central to the approach is formation of a 2,4-syn cyanohydrin from cyanide addition onto an aldehyde through a proposed seven-membered ring chelate using a bidentate Lewis acid. In addition, a highly diastereoselective Mukaiyama aldol reaction, an intramolecular radical atom cyclization, and thioaminal formation are used to generate this novel molecule. A series of related nucleoside analogues are being tested as antiviral and anticancer agents.

Full text of DOI:10.24820/ark.5550190.p010.832

The Free Internet Journal
for Organic Chemistry
Paper
Archive for
Arkivoc 2019, part iv, 0-0
Organic Chemistry
to be inserted by editorial office
Synthesis of nucleoside analogues using acyclic diastereoselective reactions
Tommy Lussier,a,b Marie-ꢀve Waltz,a Garrett Freure,a Philippe Mochirian,a Starr Dostie,a
Michel Prévost,a and Yvan Guindon*a,b
a Bio-organic Chemistry Laboratory, Institut de Recherches Cliniques de Montréal (IRCM), Montréal,
Québec, H2W 1R7, Canada
b Department of Chemistry, Université de Montréal, Montréal, Québec, H3C 3J7, Canada
Email: yvan.guindon@ircm.qc.ca
This paper is dedicated to Professor Stephen Hanessian, a mentor, colleague and friend
Received 12-03-2018
Accepted 03-11-2019
Published on line 04-29-2019
Abstract
The design of novel xylo-like nucleoside analogues bearing a C3’ all-carbon quaternary center and a C2’-
hydroxy substituent is described. Synthesis of this scaffold makes use of highly diastereoselective trans-
formations on acyclic substrates. Central to the approach is formation of a 2,4-syn cyanohydrin from cyanide
addition onto an aldehyde through a proposed seven-membered ring chelate using a bidentate Lewis acid. In
addition, a highly diastereoselective Mukaiyama aldol reaction, an intramolecular radical atom cyclization, and
thioaminal formation are used to generate this novel molecule. A series of related nucleoside analogues are
being tested as antiviral and anticancer agents.
Keywords: Nucleoside analogues, xylo-like scaffolds, diastereoselective, acyclic, cyanohydrin, all-carbon
quaternary stereo-center
DOI: https://doi.org/10.24820/ark.5550190.p010.832
Page 1
©ARKAT USA, Inc

Arkivoc 2019, iv, 0-0
Lussier. T. et al.
Introduction
The implication of endogenous nucleosides and nucleotides in numerous biological pathways has, not
surprisingly, inspired the development of various analogues as inhibitors of tumor growth and viral
replication.1,2,3 Exploring the biological profiles of novel nucleoside analogues remains crucial, as shown by the
recent approval of highly efficient antiviral drugs.4 We have initiated the syntheses of novel nucleoside
analogues possessing an all-carbon quaternary stereogenic center at C3’.5-7 It is proposed that this chiral
center could enhance target specificity in addition to providing opportunities for the incorporation of different
pharmacophores. As illustrated in Figure 1, the hydroxymethyl substituent at C3’ can have either a xylo/lyxo-
(β-face) or ribo/arabino- (α-face) like orientation. The syntheses of C2’-fluoro analogues in which the
hydroxymethyl substituent is located on the α-face (ribo-like scaffolds) has been previously reported by our
group.8 Herein, we describe the synthesis of xylo-like analogues with a C2’-hydroxy group. Incorporation of a
C3’-hydroxymethyl substituent with a β-orientation is a feature of apio-nucleosides, a class of analogues in
which the hydroxymethyl normally found at C4’ is shifted to C3’.9-11 Presently, our scaffolds are being tested
for their antiviral and anticancer properties; however, this novel xylo-like scaffold may also show potential in
the design of new fungicides12 and insecticides,13 as antimicrobial agents14 and acetylcholinesterase
inhibitors15 all of which contain a xylo-furanoside core.
Figure 1. Nucleoside analogues bearing an all-carbon stereogenic center at C3’.
To construct our novel scaffold (1), a series of diastereoselective acyclic transformations were developed
(Scheme 1). Using our two-step acyclic approach for the synthesis of nucleoside analogues, 1’,2’-trans
furanoside 2, was formed from a kinetically controlled intramolecular cyclization of chiral thioaminal 3. This
1,2-syn thioaminal resulted from diastereoselective nucleobase addition onto dithioacetal 4.
Scheme 1. Retrosynthetic analysis of xylo-like analogues.
Page 2
©ARKAT USA, Inc

Arkivoc 2019, iv, 0-0
Lussier. T. et al.
Central to our synthetic approach was a Lewis acid controlled diastereoselective cyanide (TMSCN) addition
onto aldehyde 6 through a proposed seven-membered ring chelate to generate the C2'-hydroxy substituent
from formation of the acyclic cyanohydrin 5. An intramolecular silicon tethered free radical-based vinylation
was used to construct the all-carbon stereogenic center in 7, the substrate of which was accessed from a
Mukaiyama aldol reaction between aldehyde 9 and enoxysilane 10.
Results and Discussion
The reaction sequence to generate the targeted family of nucleoside analogues began with construction of the
all-carbon quaternary center (Scheme 2). The key precursor 8a,b for the intramolecular radical atom transfer
cyclization was efficiently accessed by a three-step sequence involving a Mukaiyama aldol reaction16,17
.
between 2,3-isopropylidene-D-glyceraldehyde 9 and enoxysilanes 10 in the presence of MgBr2 OEt2.7
Treatment of the crude reaction mixture with HF-pyridine was necessary to remove undesired TMS protection
of the oxygen at C3. The vinyldimethylchlorosilane moiety was then installed on the resulting free alcohols to
provide the 3,4-anti (8a,b) and 3,4-syn (11a,b) bromides in a 10:1 ratio and excellent yield (52%) over the
three steps. Preference for the 3,4-anti stereochemistry has been proposed to occur through a Felkin-Ahn
transition state.7,18-21 The steric hindrance imposed by the isopropylidene moiety of aldehyde 9 is likely to
prohibit chelate formation between the aldehyde and α-oxygen.
Scheme 2. Synthesis of the all-carbon quaternary center in 12.
The free radical tandem cyclization/elimination reaction developed by our laboratory22 was then
performed on 8a,b in the presence of BEt3/O2 (Scheme 2). The reaction was shown to proceed through a five-
membered ring intermediate A (5-exo-trig) bearing a mixture of primary bromides.22 The stereochemistry of
the newly formed quaternary center was proposed to originate from transition state A that minimizes
intramolecular dipole-dipole interactions and allylic 1,3-strain.23 The five-membered silyloxy ether
intermediates (A) were cleaved upon treatment with 3HF·NEt3 to give the 2,3-syn product 12 as the only
observable diastereomer (>20:1) in 82% yield (see supporting information for stereochemical proofs).
Page 3
©ARKAT USA, Inc

Arkivoc 2019, iv, 0-0
Lussier. T. et al.
Derivatization of 12 towards aldehyde 6 was achieved by first carrying out silylation of the secondary
alcohol (Scheme 3). Reduction of the methyl ester and subsequent benzoylation generated the protected
primary alcohol 13 in 68% yield over three steps. Cleavage of the acetonide and oxidation of the 1,2-diol using
periodic acid led to an aldehyde that was immediately reduced to the corresponding primary alcohol 14 (85%
yield over two steps), which was then protected with a benzyl group to give 15. Deprotection of the primary
benzoate with DIBAL-H followed by DMP oxidation provided aldehyde 6.
Scheme 3. Synthesis of aldehyde 6 bearing an α-quaternary center and a β-hydroxy group.
The diastereoselective addition of cyanide24,25 onto aldehyde 6 was next studied. The desired xylo-like
scaffold of the targeted nucleoside analogue (1) required a syn stereochemistry between the substituents at
C2 and C4 of the resulting cyanohydrin (5). 1,2-Induction using a monodentate Lewis acid (TS B and TS C,
Scheme 4) was expected to be poor, since two of the substituents of the quaternary center (methyl and vinyl)
are sterically similar. The possibility of using the stereogenic secondary β-hydroxy group of the acyclic
aldehyde was therefore considered.
Scheme 4. Transition states for diastereoselective cyanohydrin formation.
Page 4
©ARKAT USA, Inc

Arkivoc 2019, iv, 0-0
Lussier. T. et al.
A bidentate Lewis acid could generate different reactive chelate intermediates. Chelation between the
β-hydroxy group and the aldehyde is expected to give preference for the undesired 2,4-anti relationship
through TS D, which avoids steric clash between the incoming nucleophile and the -CH2OBn found in TS E (2,4-
syn predictive transition state). However, the presence of the α-quaternary center could decrease the energy
difference between TS D and TS E, the former having two gauche interactions between the substituents of the
α- and β-stereogenic centers. Formation of a seven-membered ring intermediate (TS F and TS G) between the
primary oxygen and the aldehyde could allow more flexibility for chelate formation and alleviate steric
interactions between the incoming nucleophile and the quaternary center. Formation of the desired 2,4-syn
cyanohydrin (TS G) in which nucleophilic attack occurs on the bottom face should be favored to avoid eclipsing
interactions between the incoming nucleophile and the axial methyl of the quaternary center in TS G or with
the β-hydroxy group in TS F.
To prevent potential competition between six- and seven-membered ring chelates, a bulky TBS group was
24
incorporated onto the β-hydroxy of aldehyde 6. Precomplexation of aldehyde 6 with an excess of MgBr2·OEt2
o
was followed by addition of the cyanide source (TMSCN) at -15 C (Scheme 5). Cyanohydrin 5 was formed in
an 8:1 ratio in favor of the 2,4 syn isomer in excellent yield (83% over two steps). It is noteworthy that the
reaction of TMSCN and the aldehyde alone in DCM resulted in recuperation of the starting material, thus
highlighting the need for a source of Lewis acid. Cyanide addition did occur in the presence of a Lewis base
(NEt3 or NH(i-Pr)2) to furnish OTMS protected cyanohydrins (results not shown), albeit with low
diastereoselectivity.26 These observations are in accordance with precedent examples demonstrating that a
Lewis acidic or basic species is needed to activate the TMSCN through formation of a pentacoordinate
siliconate ion.27,28
Scheme 5. Synthesis of 2,4-syn cyanohydrin.
o
To validate our initial hypotheses for 2,4-syn selectivity, a model study was undertaken at 0 C (Table 1).
As can be seen in entry 1, a 6:1 ratio in favor of the syn cyanohydrin was obtained at this temperature. When
.
the reaction was performed with a monodentate Lewis acid, BF3 OEt2, an expected low diastereoselectivity of
1.5:1 was observed in favor of the 2,4-syn product (entry 2). Interestingly, when the TBS β-hydroxy protecting
group was replaced by a benzyl or p-methoxybenzyl group, (aldehydes 17 and 19), preference for the 2,4-syn
cyanohydrin was maintained (entries 3 and 4) with MgBr2·OEt2, even though competing TS D could be at play.
With aldehyde 21, bearing a free β-hydroxy group (entry 5), a reversal of selectivity in favor of the 2,4-anti
product was indeed noted suggesting reaction through TS D.
Suppressing the possibility of creating a seven-membered ring chelate by replacing the primary benzyl
protecting group with a bulky silyl ether, as in aldehyde 23, abolished the diastereoselection noted before
(1.5:1, entry 6). Similarly, when the benzyl ether was replaced by its carbon equivalent as in 25, a decrease in
selectivity was observed (2.5:1, entry 7). To ensure that this loss of selectivity was not the result of having an
α-gem-dimethyl instead of the stereogenic center, we prepared 27 and observed a high syn preference (11:1
entry 8 versus 6:1 entry 1) which suggests a greater interaction between the incoming nucleophile and olefin
Page 5
©ARKAT USA, Inc

Arkivoc 2019, iv, 0-0
Lussier. T. et al.
in TS G. Taken together, these results support the intermediacy of a 7-membered ring chelate (TS G)29-31 in
inducing 2,4-syn diastereoselectivity for cyanohydrin formation in the presence of MgBr2·OEt2.
Interestingly, with the use of a titanium Lewis acid (Table 1, entries 9-13), formation of the 2,4-anti
cyanohydrin could be favored. When aldehyde 19 bearing a β-PMB was reacted with 1.1 equivalents of
TiCl3(OiPr), a 1:1 ratio of syn and anti cyanohydrins were formed (entry 9) in which the β-PMB was cleaved.
Upon increasing the equivalents of TiCl3(OiPr) to 2.5 (entries 10 and 11) a 1:6 ratio was obtained in favor of the
2,4-anti diol 22b. Not surprisingly, with a β-OTBS, preference for the 2,4-syn cyanohydrin 5a was maintained
(3:1 ratio, entry 12), favoring cyanation through 7-membered chelate TS G or monodentate activation.
Table 1. Diastereoselective cyanohydrin formation.
Entry Aldehydea
L.A.
Equiv. L.A.
5.0
R5
R4
R3
Ratio (a:b)b Cyanohydrin Yield (%)
1
2
6
MgBr2·OEt2
BF3·OEt2
OBn
OBn
OBn
OBn
OBn
OTBS vinyl
OTBS vinyl
OBn vinyl
OPMB vinyl
OH vinyl
6:1
1.5:1
8:1c
8:1
5a,b
5a,b
79
63
81
93
89
93
82
79
ND
59
49
68
91
6
1.5
3
17
19
21
23
25
27
19
19
21
6
MgBr2·OEt2
MgBr2·OEt2
MgBr2·OEt2
MgBr2·OEt2
MgBr2·OEt2
MgBr2·OEt2
TiCl3(OiPr)
TiCl3(OiPr)
TiCl3(OiPr)
TiCl3(OiPr)
TiCl3(OiPr)
5.0
18a,b
20a,b
22a,b
24a,b
26a,b
28a,b
22a,bd
22a,bd
22a,b
5a,b
4
5.0
5
5.0
1:4
6
5.0
OTBDPS OTBS vinyl
CH2CH2Ph OTBS methyl
1.5:1
2.5:1
11:1
1:1
7
5.0
8
5.0
OBn
OBn
OBn
OBn
OBn
OBn
OTBS methyl
OPMB vinyl
OPMB vinyl
OH vinyl
9
1.1
10
11
12
13
2.5
1:6
2.5
1:6
2.5
OTBS vinyl
OBn vinyl
3:1
17
2.5
1:1c
18a,b
a
Synthesis of racemic aldehydes 6, 17, 19, 21, 23, 25 and 27 is described in the experimental section along with
proofs of structure in the supporting information. The two cyanohydrin diastereomers were separated,
deprotected to the corresponding diols and then protected as an acetonide. The relative stereochemistry of the
syn and anti-acetonides was determined from 1D NOESY and the 13C chemical shifts of the acetal carbon and the
1
gem-dimethyl substituents.b 2,4-Syn:2,4-anti ratios determined by H NMR analysis of the crude reaction mixture.
c Relative stereochemistry not determined in this case. d PMB-cleaved, resulting in diol product.
NMR Studies. To help elucidate the preference for 2,4-anti cyanohydrin formation with aldehydes 19 (β-
OPMB) and 21 (β-OH) in the presence of 2.5 equivalents of TiCl3(OiPr) (entries 10 and 11), low temperature 13C
Page 6
©ARKAT USA, Inc

Arkivoc 2019, iv, 0-0
Lussier. T. et al.
NMR spectra of the complexed aldehydes were acquired in CD2Cl2 (Figure 2). The first observation made was
13
that both aldehydes resulted in similar C spectra upon addition of 1.1 equivalents of TiCl3(OiPr), which
indicates that the β-PMB of aldehyde 19 is cleaved before addition of the nucleophile.32 Complex spectra (not
shown) were obtained with three new peaks in the carbonyl region. It is likely that these correspond to
different intermediates that react unselectively to give mixtures of diastereomers (Table 1, entry 9). However,
in the presence of 2.5 equivalents of TiCl3(OiPr) (Figure 2, upper spectrum) there is clearly only one complexed
carbonyl species with a significant downfield (11.5 ppm) signal. In addition, the carbons corresponding to C3,
C4 and C5 are also all shifted downfield, which supports their involvement in complex formation.
Figure 2. 13C NMR spectra of aldehyde 21 with 0.0 and 2.5 equiv. of TiCl3(OiPr) at 0 °C in CD2Cl2.
13
Although an X-ray structure of this titanium complex has yet to be determined, the above preliminary C
NMR spectra support formation of a complex as in intermediate E (Scheme 6). Formation of this intermediate
is supported by Gau’s studies of titanium complexes,33 where he noted the prevalence of hexacoordinated
species. In addition, these studies suggested that the binding ability of various chemical entities to titanium
-
13
was OiPr > Cl- > THF > Et2O > PhCHO > µ-Cl- > RCO2M. Based on the C NMR data, the first step in the
complexation of TiCl3(OiPr) with aldehydes 19 and 21 is formation of a covalent bond between the oxygen at
C3 and the titanium resulting in intermediate B (Scheme 6). Following Gau’s study, the second oxygen to
coordinate would be the oxygen at C4 resulting in intermediate C in which the carbonyl is uncoordinated.
Page 7
©ARKAT USA, Inc

Arkivoc 2019, iv, 0-0
Lussier. T. et al.
Scheme 6. Transition state for 2,4-anti cyanohydrin formation with 2.5 equivalents of TiCl3(OiPr).
13
Although carbonyl activation is not necessary for cyanation to occur, C NMR studies indicate that it is
indeed complexed with the titanium. Upon addition of a second equivalent of TiCl3(OiPr), intermediate D
could be formed, but monodentate activation is not likely to provide high diastereoselectivities, as observed
with 1.1 equivalents of TiCl3(OiPr) (Table 1, entry 9). Formation of intermediate E in which both titaniums are
coordinated to the oxygen at C3 would be consistent with the need for 2.5 equivalents of TiCl3(OiPr) to reach
higher levels of diastereoselectivity. Various titanium complexes were examined by density functional theory
(DFT) calculations in Gaussian 09 (D.01) with tight SCF convergence34 using the M062X35/6-31G* level of
theory in DCM with the polarizable continuum model (PCM).36 Intermediate E in which the isopropoxide
ligands are located trans to the C1-aldehyde and C4-OBn group was of lowest energy. Through NBO analysis, a
weak interaction was observed between the chloride ligand and the C4’-Ti thus both titanium centers exist as
hexacoordinate species. Although, it is also possible to form a bicyclic [3.2.1]-type complex with 2.5
equivalents of TiCl3(OiPr), as previously proposed,37 our preliminary 13C NMR data is consistent with formation
of intermediate E through initial displacement of a chloride ligand. Preferential attack of the cyanide opposite
the β-alkyl chain in TS H would result in formation of the 2,4-anti cyanohydrin 22b. Interestingly, when
aldehyde 17 bearing a β-OBn group was reacted in the presence of 2.5 equivalents of TiCl3(OiPr) (entry 13,
Table 1), a 1:1 ratio of syn and anti cyanohydrins 18a,b was obtained. The presence of this benzyl protecting
group results in a reaction pathway not involving intermediate E.
Investigation of this cyanation reaction has demonstrated that the choice of Lewis acid and β-protecting
group are key to reach high levels of diastereoselectivity in favor of the 2,4-syn or 2,4-anti cyanohydrin
allowing access to either the xylo-like (this manuscript) or the lyxo-like nucleoside analogues. In addition, this
cyanation reaction highlights the potential for other stereoselective nucleophilic additions onto aldehydes
possessing an α-stereogenic center for which there are few literature examples.38,39
Page 8
©ARKAT USA, Inc

Arkivoc 2019, iv, 0-0
Lussier. T. et al.
To generate the novel nucleoside scaffold, the C2-protected 2,4-syn cyanohydrin 16 was first reduced with
DIBAL-H and then transformed into di(ethylthio)acetal 4 in 70% yield (Scheme 7).
Scheme 7. Acyclic approach for the synthesis of nucleoside analogues.
At this point in the strategy, we made use of our novel two-step acyclic approach for the synthesis of
nucleoside analogues,40 the mechanism of which has been examined in detail using DFT calculations.8,41 We
have recently reported the use of this strategy with a C3-quaternary center and a fluoride at C2,8 however,
this is the first report of using this strategy with a thioaminal bearing a C2-hydroxy and a C3-quaternary
center. An essential aspect of this strategy is the diastereoselective synthesis of a 1,2-syn thioaminal (29) from
a dithioacetal (4). Activation of this acyclic dithioacetal with iodine and addition of silylated nucleobase
(thymine or uracil) provided the 1,2-syn thioaminals in excellent diastereoselectivity (only one isomer could be
detected by 1H NMR) and yield. Formation of the 1,2-syn thioaminal proceeds through a SN2-like mechanism in
which the initially formed halothioether adopts a conformational preference orienting the C2-OTBS and the
thioether moiety in close proximity to one another to maximize R−C2 and H−C2 sigma donation to the
electron poor thiacarbenium intermediate in TS I. The presence of the counteranion (I-) stabilizes this
transition state and prefers to be located on the opposite side of the incoming nucleobase.8,41 Selective
removal of the less hindered C4-TBS protecting group provided the necessary thioaminals 30 and 31 in
excellent yields. The next key step of our acyclic approach involves a stereospecific displacement of the
activated sulfur of the thioaminal by the C4-hydroxy with inversion of configuration (O4’-C1 cyclization). This
provided the D-1’,2’-trans furanosides 32 (thymine, 71% yield) and 33 (uracil, 80% yield). Proof of structure for
the nucleoside analogues was determined by 2D NOESY experiments (see supporting information).
Transformation of the monosubstituted alkene of 32 and 33 into the desired primary alcohol was
accomplished in five steps (Scheme 8). This monosubstituted alkene could serve as the starting point for a
variety of chemical modifications to add heteroatoms and diverse functionalities. In this study, it was
transformed into an hydroxymethyl group.
Page 9
©ARKAT USA, Inc

Arkivoc 2019, iv, 0-0
Lussier. T. et al.
Scheme 8. Synthesis of xylo-like nucleoside analogues.
Dihydroxylation using osmium tetroxide followed by oxidative cleavage of the diol resulted in the
corresponding aldehyde that was reduced using lithium borohydride providing the C3’-hydroxymethyl
substituent. Removal of the C2’-TBS provided scaffolds 34 and 35 in 59% yield for these four steps. The desired
xylo-like nucleoside analogues (36 and 37) were formed after removal of the primary benzyl protecting
groups.
Conclusions
The synthesis of a novel class of xylo-like nucleoside analogues bearing a stereogenic quaternary center at C3’
has been described. This acyclic synthetic route relies on highly diastereoselective chemical transformations
investigated in our laboratory: an anti selective Mukaiyama aldol reaction, a syn selective intramolecular
radical transfer cyclization, formation of a syn selective cyanohydrin followed by the synthesis and cyclization
of a syn thioaminal. A key element of this route is the cyanide addition onto aldehydes activated through
formation of proposed 7-membered ring chelates. These analogues and other molecules of this family are
being tested for their antiviral and antiproliferative properties. The results of these tests will be reported in
due course.
Experimental Section
General Comments. All reactions requiring anhydrous conditions were carried out under an atmosphere of
nitrogen or argon in flame-dried glassware using standard syringe techniques. All anhydrous solvents were
dried with 4 Å molecular sieves prior to use. The 4 Å molecular sieves (1–2 mm beads) were activated by
o
heating at 180 C for 48 hours under vacuum prior to adding to new bottles of solvent purged with argon.
Commercially available reagents were used as received. Flash chromatography was performed on silica gel 60
(0.040 – 0.063 mm) using forced flow (flash chromatography) of the indicated solvent system or an automated
flash purification system Biotage Isolera One (version 1.3.6). Analytical thin-layer chromatography (TLC) was
carried out on pre-coated (0.25 mm) silica gel aluminum plates. Visualization was performed with U.V. short
wavelength and/or revealed with ammonium molybdate or potassium permanganate solutions. 1H NMR
spectra were recorded at room temperature on a 500 MHz Varian Unity INOVA NMR spectrometer. The data
are reported as follows: chemical shift in ppm referenced to residual solvent (CDCl3 δ 7.26 ppm), multiplicity (s
= singlet, d = doublet, dd = doublet of doublets, ddd = doublet of doublets of doublets, t = triplet, td = triplet of
Page 10
©ARKAT USA, Inc

Arkivoc 2019, iv, 0-0
Lussier. T. et al.
13
doublets, m = multiplet, app = apparent), coupling constants (Hz), and integration. C NMR spectra were
recorded at room temperature using 100.6 (Varian VXR 400 NMR) or 126 MHz. The data are reported as
follows: chemical shift in ppm referenced to residual solvent (CDCl3 δ 77.16 ppm). Infrared spectra were
recorded on a FTIR ABB Bomen (MB series) or a Bruker Platinum ATR (Alpha II series) spectrophotometer from
a thin film of purified product and signals are reported in cm-1. Mass spectra were recorded through
electrospray ionization (ESI) positive ion mode using a Thermo Fischer LTQ Orbitrap XL. A Q exactive mass
analyzer was used for HRMS measurements and were done by the Plateforme de découvertes en protéomique
at l’Institut de Recherches Cliniques de Montréal (IRCM). Optical rotations were measured at room
temperature from the sodium D line (589 nm) using a PerkinElmer 343 polarimeter and CDCl3 as solvent unless
otherwise noted and calculated using the formula: [α]D =(100)αobs/(ℓ·(c)), where c = (g of substrate/100 ml of
solvent) and ℓ = 1 dm. The characterization of chemical structures from X-ray data has been done at the
Université de Montréal X-ray diffraction laboratory. Proofs of structure can be found in the supporting
information.
General Procedure A: Reduction of ester
To a solution of ester in dry CH2Cl2 (67 mL, 0.20 M) at –40 oC, DIBAL-H (3.0 equiv.) was added. The solution was
stirred until the ester (1.0 equiv.) was all consumed (1h30 at –40 oC) as determined by TLC. MeOH was added
at –40 oC until gas formation ceased. An aqueous solution of potassium sodium tartrate was added, and the
reaction mixture was warmed to room temperature. The aqueous layer was extracted with Et2O (3x). The
organic layers were combined, dried over MgSO4, filtered and concentrated in vacuo.
General Procedure B: Oxidation of alcohol
To a solution of oxalyl chloride (1.3 equiv.) in anhydrous CH2Cl2 (0.10 M) at –78 oC, dimethyl sulfoxide (2.3
equiv.) was added dropwise. The solution was stirred for 20 minutes at which point the alcohol (1.0 equiv.), as
a 0.40 M solution in anhydrous CH2Cl2, was added followed by stirring at –78 oC for 1h. Triethylamine (5.0
equiv.) was added and the reaction mixture was warmed to room temperature over 45 minutes. An aqueous
solution of NH4Cl was added and the aqueous layer was extracted with Et2O (3x). The organic layers were
combined, dried over MgSO4, filtered and concentrated in vacuo.
General Procedure C: Cyanohydrin formation
To a solution of aldehyde (1.0 equiv.) in anhydrous CH2Cl2 (0.10 M) at 0 C, the appropriate Lewis acid,
o
MgBr2·OEt2 (5.0 equiv.), BF3·OEt2 (1.5 equiv.), or TiCl3(OiPr) (1.1 or 2.5 equiv.), was added. The reaction
mixture was stirred 5 minutes for precomplexation. TMSCN (2.0 equiv.) was then added. The solution was
stirred until the aldehyde was all consumed, 1h at 0 oC, as determined by TLC. An aqueous solution of NaHCO3
was added and the aqueous layer was extracted with Et2O (3x). The organic layers were combined, dried over
MgSO4, filtered and concentrated in vacuo.
TiCl3(OiPr) was prepared by mixing one equivalent of Ti(OiPr)4 with three equivalents of TiCl4 in DCM.42
Preparation of silylated nucleobases
To a suspension of the nucleobase in HMDS (2.7 equiv.) under inert atmosphere, (NH4)2SO4 (0.10 equiv.) was
added. The reaction mixture was refluxed until a clear solution was obtained (typically three hours). Upon
cooling to room temperature, the solution was placed under high vacuum for approximately 1 hour to remove
excess HMDS. A solution of the silylated nucleobase was made in dichloroethane.
Compounds 8a,b and 12 from Scheme 2:
(–)-Methyl (2R,3R)-2-bromo-3-{[dimethyl(vinyl)silyl]oxy}-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpro-
panoate (8a) and (+)-methyl (2S,3R)-2-bromo-3-{[dimethyl(vinyl)silyl]oxy}-3-((R)-2,2-dimethyl-1,3-dioxolan-
o
4-yl)-2-methylpropanoate (8b): To a 0 C solution of crude methyl (3R)-2-bromo-3-((R)-2,2-dimethyl-1,3-
dioxolan-4-yl)-3-hydroxy-2-methylpropanoate7 (4.8 g, 16 mmol, 1.0 equiv.) in CH2Cl2 (40 mL, 0.40 M),
Page 11
©ARKAT USA, Inc

Arkivoc 2019, iv, 0-0
Lussier. T. et al.
imidazole (3.3 g, 48 mmol, 3.0 equiv.) was added in one portion. Upon complete dissolution of imidazole,
chloro(dimethyl)vinylsilane (3.14 mL, 20.8 mmol, 1.30 equiv.) was added dropwise. The reaction was then
1
warmed to room temperature and stirring continued for 16 hours at which point H NMR showed complete
conversion of starting material. The reaction mixture was quenched with water. The aqueous layer was
extracted with CH2Cl2 (3 × 25 mL), the organic layers were combined, washed with brine, dried over MgSO4,
filtered and concentrated in vacuo to afford the crude product as a dark yellow oil. Coevaporation with
toluene (2x) and purification using a silica pad (Hexanes/Et2O, 30:70) provided 8a,b (3.2 g, 52% yield over 3
steps, 3,4-anti : 3,4-syn 10:1) as a light-yellow oil. The minor product from the aldol reaction (11a,b) could not
[]25
be separated. 8a: Rf = 0.37 (Hexanes/Et2O 90:10);
–2.7 (c= 2.0, CH2Cl2); Molecular formula: C14H25BrO5Si;
D
MW: 381.34; IR (neat) νmax 2985, 2953, 1744, 1250, 1053 cm-1; H NMR (500 MHz, CDCl3) δ 6.15 (dd, J 20.3,
1
14.9 Hz, 1H), 6.02 (dd, J 14.9, 3.9 Hz, 1H), 5.75 (dd, J 20.3, 3.8 Hz, 1H), 4.62 – 4.57 (m, 2H), 3.98 – 3.91 (m, 2H),
13
3.78 (s, 3H), 1.77 (s, 3H), 1.46 (s, 3H), 1.35 (s, 3H), 0.24 (s, 3H), 0.23 (s, 3H) ppm; C NMR (126 MHz, CDCl3) δ
170.6, 137.7, 133.4, 108.1, 76.9, 75.9, 64.6, 61.4, 53.4, 26.2, 24.5, 23.8, -0.9, -1.3 ppm; HRMS calcd for
C14H25BrO5SiNa [M+Na+]: 403.0547; found 403.0533 (-3.5 ppm). 8b (6:1 mix with 3,4-syn product): Rf = 0.21
[]25
(Hexanes/Et2O 90:10);
+11 (c= 0.8, CH2Cl2); IR (neat) νmax 2987, 2952, 1744, 1254, 1104 cm-1; 1H NMR (500
D
MHz, CDCl3) δ 6.25 (dd, J 20.4, 14.9 Hz, 1H), 6.07 (dd, J 14.9, 3.7 Hz, 1H), 5.82 (dd, J 20.4, 3.7 Hz, 1H), 4.33 (d, J
7.2 Hz, 1H), 4.09 (dd, J 8.1, 6.5 Hz, 1H), 4.02 (dd, J 13.5, 6.5 Hz, 1H), 3.81 – 3.79 (m, 1H), 3.76 (s, 3H), 1.89 (s,
13
3H), 1.35 (s, 3H), 1.29 (s, 3H), 0.34 (s, 3H), 0.31 (s, 3H) ppm; C NMR (126 MHz, CDCl3) δ 170.8, 137.7, 133.7,
109.8, 78.4, 76.4, 68.3, 64.9, 52.9, 26.1, 25.1, 22.2, -0.7, -1.0 ppm; HRMS calcd for C14H25BrO5SiNa [M+Na+]:
403.0547; found 403.0533 (-3.5 ppm).
(–)-Methyl (S)-2-((S)-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl)(hydroxy)methyl]-2-methylbut-3-enoate (12): To a
solution of the α-bromo ester 8a,b (2.0 g, 5.2 mmol, 1.0 equiv.) in toluene (11 mL, 0.50 M) at 0 °C, BEt3 (5.2
mL, 1.0 M, 1.0 equiv.) was added with a syringe pump over 4 hours. After completion of the reaction,
ethanolamine (0.90 mL, 16 mmol, 3.0 equiv.) was added. The mixture was stirred for 30 minutes before it was
transferred to a plastic vial and treated with 3HF·NEt3 (1.3 mL, 7.9 mmol, 1.5 equiv.) at 0 °C. The mixture was
stirred at room temperature overnight. The crude solution was transferred dropwise into a cold solution of
saturated NaHCO3. The aqueous layer was extracted with Et2O (2x), the organic layers were combined, dried
over MgSO4, filtered and concentrated in vacuo. The crude product (2,3-syn, dr >20:1) was purified by flash
chromatography on silica gel (Hexanes/Et2O, 60:40) to give 12 (1.05 g, 82%) as a colorless oil. The minor 3,4-
syn product from the Mukaiyama aldol (not characterized) could be separated. 12: Rf = 0.3 (Hexanes/EtOAc,
[]25
1
65:35);
-20 (c= 1.1, CH2Cl2); Molecular formula: C12H20O5; MW: 244.29; IR (neat) νmax 1722 cm-1; H NMR
D
(500 MHz, CDCl3) δ 6.12 (dd, J 17.6, 10.8 Hz, 1H), 5.32 (d, J 10.8 Hz, 1H), 5.25 (d, J 17.6 Hz, 1H), 4.08 – 3.99 (m,
3H), 3.96 – 3.91 (m, 1H), 3.70 (s, 3H), 1.37 (s, 3H), 1.35 (s, 3H), 1.32 (s, 3H) ppm, OH signal missing possibly due
to exchange in CDCl3; 13C NMR (126 MHz, CDCl3) δ 175.0, 138.4, 117.3, 109.1, 76.1, 75.6, 67.2, 52.8, 52.4, 26.4,
25.4, 15.2 ppm; HRMS calcd for: C12H20O5Na [M+Na+]: 267.1203; found 267.1204 (+0.4 ppm).
Compounds 13, 14, 15 and 6 from Scheme 3:
(+)-(R)-2-[(S)-((tert-Butyldimethylsilyl)oxy]-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-methylbut-3-en-1-
yl benzoate (13): To a solution of secondary alcohol 12 (4.9 g, 20 mmol, 1.0 equiv.) in CH2Cl2 (25 mL, 0.80 M)
o
at 0 C pyridine (3.2 mL, 40 mmol, 2.0 equiv.) and TBSOTf (5.5 mL, 24 mmol, 1.2 equiv.) were added. The
resulting mixture was stirred at room temperature for 16 hours before addition of Et2O/Hexanes (1:1, 25 mL)
and saturated aqueous NH4Cl (30 mL). After stirring vigorously for 10 minutes, the layers were separated, and
the aqueous layer extracted with Et2O/Hexanes (1:1, 2 x 30 mL). The organic fractions were combined and
washed successively with 1N HCl (2 x 40 mL), water and brine, dried over MgSO4, filtered and concentrated in
vacuo. The crude residue (7.2 g, 99% yield) was coevaporated with toluene (2 x 10 mL) and used directly in the
Page 12
©ARKAT USA, Inc

Arkivoc 2019, iv, 0-0
Lussier. T. et al.
next reaction. A solution of the crude ester (7.2 g, 20 mmol, 1.0 equiv.) in CH2Cl2 (40 mL, 0.50 M) was cooled
to –40 oC (MeCN/dry ice bath) followed by addition of DIBAL-H (45 mL, 45 mmol, 2.2 equiv.) over 10 minutes.
After stirring 90 minutes at –40 oC, a saturated solution of aqueous Rochelle salt (60 mL) was slowly added
followed by saturated aqueous Na2CO3 (10 mL) and Et2O (40 mL). The biphasic mixture was warmed to room
temperature and vigorously stirred until both phases were clear (about 2 hours). The aqueous layer was
extracted with Et2O (2 × 40 mL) and the combined organic fractions were washed with saturated aqueous
Na2CO3 followed by brine, dried over MgSO4, filtered and concentrated in vacuo to afford the crude primary
alcohol as a colorless oil which was used directly in the next step. The crude primary alcohol (6.6 g, 20 mmol,
1.0 equiv.) was dissolved in CH2Cl2 (20 mL, 1.0 M) and pyridine (6.5 mL, 80 mmol, 4.0 equiv.) and DMAP (0.49
g, 4.0 mmol, 0.20 equiv.) were added. The resulting reaction mixture was cooled to 0 oC and benzoyl chloride
(2.8 mL, 24 mmol, 1.2 equiv.) was added dropwise. The reaction mixture was slowly warmed to room
temperature and stirred for 5 hours before being cooled to 0 oC followed by addition of ethylenediamine (0.94
mL, 14 mmol, 0.70 equiv.). After stirring 45 minutes, CH2Cl2 was evaporated and the residue diluted with Et2O,
loaded on a silica pad and eluted with Hexanes/EtOAc (1:1) to afford the crude product as an oil. Purification
by flash column chromatography provided 13 as a colorless oil (5.9 g, 68% yield over 3 steps). Rf = 0.68
[]25
(Hexanes/EtOAc, 80:20);
+24 (c = 2.6, CH2Cl2); Molecular formula: C24H38O5Si; MW: 434.25; IR (neat) νmax
D
1722 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.08 – 8.02 (m, 2H), 7.61 – 7.55 (m, 1H), 7.50 – 7.43 (m, 2H), 5.99 (dd, J
17.7, 11.0 Hz, 1H), 5.26 – 5.18 (m, 2H), 4.27 – 4.20 (m, 4H), 3.81 (d, J 7.5 Hz, 2H), 1.45 (s, 3H), 1.32 (s, 3H), 1.22
(s, 3H), 0.93 (s, 9H), 0.16 (s, 3H), 0.07 (s, 3H) ppm; C NMR (126 MHz, CDCl3) δ 166.5, 139.0, 133.1, 130.4,
13
129.6, 128.6, 116.4, 110.1, 107.4, 76.2, 75.3, 69.4, 64.4, 45.1, 26.3, 24.9, 18.9, 18.6, -3.0, -4.4 ppm; HRMS calcd
for: C24H38O5SiNa [M+Na+]: 457.2381; found 457.2374 (-1.5 ppm).
(+)-(R)-2-{(S)-1-[(tert-Butyldimethylsilyl)oxy]-2-hydroxyethyl}-2-methylbut-3-en-1-yl benzoate (14): To a 0 oC
solution of acetal 13 (5.2 g, 12 mmol, 1.0 equiv.) in EtOAc (120 mL, 0.10 M), periodic acid (4.1 g, 18 mmol, 1.5
equiv.) was added in one portion. The resulting heterogeneous mixture was stirred vigorously for 15 minutes
at 0 oC and then at room temperature until complete conversion (typically 3-4 hours by TLC monitoring). The
mixture was diluted with Et2O (100 mL) and slowly poured into cold saturated aqueous Na2S2O3 (75 mL) and
saturated aqueous Na2CO3 (10 mL). After vigorously stirring 30 minutes, the aqueous layer was extracted with
Et2O (1 × 50 mL) and the combined organic fractions were washed with brine, dried over MgSO4, filtered and
concentrated in vacuo to afford the aldehyde (4.4 g, 100% yield, crude) which was used directly in the next
step. 1H NMR (500 MHz, CDCl3) δ 9.59 (d, J 3.1 Hz, 1H), 8.04 – 7.99 (m, 2H), 7.63 – 7.56 (m, 1H), 7.52 – 7.43 (m,
2H), 6.10 (dd, J 17.7, 11.0 Hz, 1H), 5.29 (d, J 11.0 Hz, 1H), 5.24 (dd, J 17.6, 0.7 Hz, 1H), 4.35 (d, J 10.8 Hz, 1H),
4.23 (d, J 10.8 Hz, 1H), 3.94 (d, J 3.1 Hz, 1H), 1.24 (s, 3H), 0.94 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H) ppm). The crude
aldehyde (4.4 g, 12 mmol, 1.0 equiv.) was dissolved in THF (60 mL, 0.20 M) and the resulting solution was
cooled to –40 oC. LiBH4 (2.0 M in THF, 6.0 mL, 12 mmol, 1.0 equiv.) was then added dropwise and the reaction
mixture stirred at –40 oC for 1 hour. The reaction was quenched by slow addition of 0.1 N HCl (60 mL) and the
biphasic mixture stirred vigorously for 30 minutes at room temperature at which point Et2O was added. The
aqueous layer was extracted with Et2O (2 × 30 mL) and the combined organic layers washed with 1 N HCl (25
mL), water and brine, dried over MgSO4, filtered and concentrated in vacuo to afford the crude primary
alcohol. Purification by flash chromatography provided 14 as a colorless oil (3.7 g, 85% yield over 2 steps): Rf =
[]25
0.37 (Hexanes/EtOAc, 80:20);
+4.8 (c=6.3, CH2Cl2); Molecular formula: C20H32O4Si; MW: 364.56; IR (neat)
D
νmax 3501, 1720, 1704 cm-1; H NMR (500 MHz, CDCl3) δ 8.08 – 8.03 (m, 2H), 7.62 – 7.55 (m, 1H), 7.50 – 7.43
(m, 2H), 6.07 (dd, J 17.7, 11.0 Hz, 1H), 5.27 – 5.16 (m, 2H), 4.30 (d, J 10.8 Hz, 1H), 4.27 (d, J 10.8 Hz, 1H), 3.85
(dd, J 5.3, 3.5 Hz, 1H), 3.75 (ddd, J 11.5, 5.7, 3.6 Hz, 1H), 3.71 – 3.64 (m, 1H), 1.21 (s, 3H), 0.94 (s, 9H), 0.15 (s,
3H), 0.10 (s, 3H) ppm, OH signal missing possibly due to exchange in CDCl3; 13C NMR (126 MHz, CDCl3) δ 166.5,
1
Page 13
©ARKAT USA, Inc

Arkivoc 2019, iv, 0-0
Lussier. T. et al.
139.8, 133.1, 130.4, 129.6, 128.6, 115.7, 76.9, 69.0, 64.3, 44.9, 26.1, 19.0, 18.4, -3.8, -4.7 ppm; HRMS calcd for
C20H33O4Si [M+H+]: 365.2143; found: 365.2165 (-6.0 ppm).
(+)-(R)-2-{(S)-2-(Benzyloxy)-1-[(tert-butyldimethylsilyl)oxy]ethyl}-2-methylbut-3-en-1-yl benzoate (15): To a
solution of primary alcohol 14 (3.7 g, 10 mmol, 1.0 equiv.) in cyclohexane/CH2Cl2 (2:1, 100 mL, 0.10 M) at 0 oC,
benzyl 2,2,2-trichloroacetimidate (2.4 mL, 13 mmol, 1.3 equiv.) and trifluoromethanesulfonic acid (0.13 mL,
1.5 mL, 0.15 equiv.) were added. The resulting suspension was stirred for 16 hours at room temperature at
which point NEt3 (0.7 mL, 5 mmol, 0.5 equiv.) was added and the volatiles removed in vacuo. Hexane was
added, and the solids filtered over Celite. Purification by flash chromatography (Hexanes/Et2O) provided 15 as
[]2D5
a colorless oil (3.8 g, 84%): Rf = 0.51 (Hexanes/EtOAc, 90:10);
+9.8 (c= 3.6, CH2Cl2); Molecular formula:
C27H38O4Si; MW: 454.68; IR (neat) νmax 2953, 2928, 2855, 1720, 1269, 1108 cm-1; H NMR (500 MHz, CDCl3) δ
8.10 – 8.03 (m, 2H), 7.61 – 7.56 (m, 1H), 7.51 – 7.43 (m, 2H), 7.42 – 7.27 (m, 5H), 6.05 (dd, J 17.7, 11.0 Hz, 1H),
5.24 – 5.17 (m, 2H), 4.54 (d, J 11.9 Hz, 1H), 4.48 (d, J 11.9 Hz, 1H), 4.34 (d, J 10.6 Hz, 1H), 4.27 (d, J 10.6 Hz, 1H),
3.99 (dd, J 6.4, 2.9 Hz, 1H), 3.67 (dd, J 10.0, 3.0 Hz, 1H), 3.39 (dd, J 10.0, 6.4 Hz, 1H), 1.22 (s, 3H), 0.92 (s, 9H),
1
13
0.11 (s, 3H), 0.09 (s, 3H) ppm ; C NMR (126 MHz, CDCl3) δ 166.6, 139.5, 138.3, 133.0, 130.6, 129.6, 128.5,
128.4, 127.8, 127.7, 115.7, 75.9, 73.6, 73.4, 69.2, 45.0, 26.1, 18.8, 18.5, -3.8, -5.0 ppm; HRMS calcd for
C27H39O4Si [M+H+]: 455.2612; found 455.2592 (-4.4 ppm).
o
(+)-(R)-2-{(S)-2-(Benzyloxy)-1-[(tert-butyldimethylsilyl)oxy]ethyl}-2-methylbut-3-en-1-ol (S1): To a –40 C
solution of benzoate 15 (3.2 g, 7.0 mmol, 1.0 equiv.) in CH2Cl2 (21 mL, 0.33M), DIBAL-H (1.0 M in hexanes, 17
mL, 17 mmol, 2.4 equiv.) was added over 10 minutes. The solution was stirred for 1 hour at –40 oC before
addition of Et2O (20 mL) followed by saturated aqueous Rochelle salt (30 mL). The biphasic mixture was
warmed to room temperature and stirred vigorously for 2 hours. The aqueous layer was extracted with Et2O (2
× 25 mL) and the combined organic fractions were washed with 0.1 N HCl, water and brine, dried over MgSO4,
filtered and concentrated in vacuo. Purification by flash chromatography provided primary alcohol S1 as a
[]25
colorless oil (1.5 g, 61% yield): Rf = 0.41 (Hexanes/EtOAc, 80:20);
+2.9 (c= 3.0, CH2Cl2); Molecular formula:
D
C20H34O3Si; MW: 350.57; IR (neat) νmax 3455, 1471, 1096 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.38 – 7.28 (m, 5H),
5.93 (dd, J 17.8, 11.0 Hz, 1H), 5.15 (dd, J 11.1, 1.2 Hz, 1H), 5.08 (dd, J 17.8, 1.3 Hz, 1H), 4.52 (d, J 11.9 Hz, 1H),
4.49 (d, J 11.9 Hz, 1H), 3.79 (dd, J 5.4, 3.9 Hz, 1H), 3.62 (dd, J 10.1, 3.8 Hz, 2H), 3.57 – 3.51 (m, 1H), 3.44 (dd, J
13
10.1, 5.5 Hz, 1H), 2.66 (s, 1H), 1.11 (s, 3H), 0.91 (s, 9H), 0.10 (s, 3H), 0.08 (s, 3H) ppm; C NMR (126 MHz,
CDCl3) δ 141.4, 138.0, 128.5, 127.84, 127.78, 114.8, 77.6, 73.5, 73.0, 68.1, 45.7, 26.1, 19.0, 18.4, -3.9, -4.9
ppm; HRMS calcd for C20H34O3SiNa [M+Na+]: 373.2169; found 373.2155 (-3.8 ppm).
(+)-(S)-2-{(S)-2-(Benzyloxy)-1-[(tert-butyldimethylsilyl)oxy]ethyl}-2-methylbut-3-enal (6): To a solution of
primary alcohol S1 (0.84 g, 2.4 mmol, 1.0 equiv.) in CH2Cl2 (24 mL, 0.10 M), Dess-Martin periodinane (DMP, 1.1
g, 2.6 mmol, 1.1 equiv.) was added. The resulting suspension was stirred for 16 hours at room temperature
before addition of saturated aqueous Na2S2O3 (20 mL). The biphasic mixture was vigorously stirred for 30
minutes. The aqueous layer was extracted with CH2Cl2 (1x20 mL), the combined organic fractions were washed
with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude aldehyde was purified by flash
chromatography (Hexanes/EtOAc) to provide 6 as a colorless oil (700 mg, 84% yield): Rf = 0.59
[]25
(Hexanes/EtOAc, 88:12);
+2.0 (c= 3.0, CH2Cl2); Molecular formula: C20H32O3Si; MW: 348.56; IR (neat) νmax
D
1726 cm-1; 1H NMR (500 MHz, CDCl3) δ 9.58 (s, 1H), 7.37 – 7.27 (m, 5H), 6.06 (dd, J 17.8, 10.9 Hz, 1H), 5.29 (d, J
10.9 Hz, 1H), 5.13 (d, J 17.8 Hz, 1H), 4.47 (d, J 11.9 Hz, 1H), 4.43 (d, J 11.9 Hz, 1H), 4.10 (t, J 5.2 Hz, 1H), 3.46
(dd, J 9.9, 5.1 Hz, 1H), 3.42 (dd, J 9.9, 5.4 Hz, 1H), 1.18 (s, 3H), 0.86 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H) ppm; C
13
NMR (126 MHz, CDCl3) δ 202.0, 137.9, 137.0, 128.5, 127.83, 127.80, 117.3, 75.5, 73.5, 72.1, 56.9, 26.0, 18.3,
14.6, -4.0, -4.9 ppm; HRMS calcd for C20H32O3SiNa [M+Na+]: 371.2013; found 371.2000 (-3.5 ppm).
Page 14
©ARKAT USA, Inc

Arkivoc 2019, iv, 0-0
Lussier. T. et al.
Compounds 5a and 16 from Scheme 5:
(–)-(2R,3R)-3-{(S)-2-(Benzyloxy)-1-[(tert-butyldimethylsilyl)oxy]ethyl}-2-hydroxy-3-methylpent-4-enenitrile
(5a), and (2S,3R)-1-(benzyloxy)-2-[(tert-butyldimethylsilyl)oxy]-3-[(S)-cyano(hydroxy)methyl]-3-methylpent-
4-en-1-ylium (5b): A solution of aldehyde 6 (700 mg, 2.01 mmol, 1.00 equiv.) in CH2Cl2 (20 mL, 0.10 M) was
cooled to –15 oC (NH4Cl/ice) before addition of MgBr2·OEt2 (2.6 g, 10 mmol, 5.0 equiv.) in one portion. After 10
minutes, TMSCN (0.50 mL, 4.0 mmol, 2.0 equiv.) was added dropwise and the resulting mixture was stirred 1
hour at –15 oC. The reaction was quenched with saturated aqueous NaHCO3 (20 mL) and the biphasic mixture
warmed to room temperature. After stirring vigorously for 15 minutes, Et2O (20 mL) was added and the
aqueous layer was extracted with Et2O (1 × 15 mL). The combined organic fractions were washed with brine,
dried over MgSO4, filtered and concentrated in vacuo to afford the crude cyanohydrin which could be used
directly for the next step. 1H NMR analysis of the crude mixture showed an 8:1 mixture of stereoisomers. Data
[]25
for the major 2,4-syn-cyanohydrin 5a (
-1.9 (c= 5.5, CH2Cl2)) correspond to that obtained from the reaction
D
of racemic aldehyde 6 with MgBr2·OEt2 at 0 oC (Table 1, entry 1) as seen below.
(+)-(2R,3R)-3-((S)-2-(Benzyloxy)-1-((tert-butyldimethylsilyl)oxy)ethyl)-2-((tert-butyldimethylsilyl)oxy)-3-methyl-
pent-4-enenitrile (16): The crude cyanohydrin 5 (755 mg, 2.01 mmol, 1.00 equiv.) was dissolved in CH2Cl2 (10
mL, 0.20 M) and the resulting solution was cooled to 0 oC followed by addition of pyridine (0.49 mL, 6.0 mmol,
3.0 equiv.) and TBSOTf (0.55 mL, 2.4 mmol, 1.2 equiv.). The reaction was stirred at 0 oC for 16 hours followed
by addition of saturated aqueous NaHCO3 (15 mL) and hexanes (15 mL). The aqueous layer was extracted with
Hexanes/Et2O (2:1, 2 × 15mL) and the combined organic fractions were washed with 0.1 N HCl followed by
brine, dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography
(Hexanes/Et2O) provided the protected cyanohydrin 16 as a single diastereoisomer (815 mg, 83% yield over
[]2D5
two steps): Rf = 0.52 (Hexanes/Et2O, 95:5);
+36 (c= 2.3, CH2Cl2); Molecular formula: C27H47NO3Si2; MW:
489.85; IR (neat) νmax 2953, 2929, 2857, 1253, 1118, 1102 cm-1; H NMR (500 MHz, CDCl3) δ 7.36 – 7.26 (m,
5H), 5.89 (dd, J 17.6, 10.9 Hz, 1H), 5.24 (dd, J 10.9, 1.0 Hz, 1H), 5.13 (dd, J 17.6, 1.2 Hz, 1H), 4.71 (s, 1H), 4.48
(d, J 11.9 Hz, 1H), 4.41 (d, J 11.9 Hz, 1H), 3.99 (dd, J 6.7, 2.5 Hz, 1H), 3.51 (dd, J 10.2, 2.6 Hz, 1H), 3.27 (dd, J
1
13
10.2, 6.7 Hz, 1H), 1.16 (s, 3H), 0.90 (s, 9H), 0.88 (s, 9H), 0.16 (s, 6H), 0.08 (s, 3H), 0.06 (s, 3H) ppm; C NMR
(126 MHz, CDCl3) δ 138.1, 137.3, 128.5, 127.7, 119.2, 117.9, 76.5, 73.4, 73.2, 67.0, 49.5, 26.2, 25.7, 18.5, 18.2,
14.9, -3.8, -5.10, -5.11, -5.3 ppm; HRMS calcd for C27H47NO3Si2Na [M+Na+]: 512.2987; found 512.2963 (-4.6
ppm).
Aldehydes 17, 19, 21, 23, 25 and 27 along with cyanohydrins 5a,b, 18a,b, 20a,b, 22a,b, 24a,b, 26a,b and
28a,b from Table 1 (racemic):
(±)-(S)-Ethyl 2-((S)-2-(Benzyloxy)-1-(tert-butyldimethylsilyloxy)ethyl)-2-methylbut-3-enoate (S2): To a
solution of (S)-methyl 2-[(S)-2-(benzyloxy)-1-hydroxyethyl]-2-methylbut-3-enoate22 (4.29 g, 16.2 mmol, 1.00
equiv.) in anhydrous CH2Cl2 (160 mL, 0.10 M) at 0 oC, 2,6-lutidine (3.8 mL, 33 mmol, 2.0 equiv.) and TBSOTf
(5.22 mL, 22.7 mmol, 1.40 equiv.) were added. The solution was stirred until the alcohol was all consumed,
1h30 at 0 oC, as determined by TLC. An aqueous solution of NH4Cl was added to the reaction mixture and the
aqueous layer was extracted with Et2O (3x). The organic layers were combined, dried over MgSO4, filtered and
concentrated in vacuo. Purification by flash chromatography using 5:95 EtOAc:Hex provided protected ester
S2 as a clear oil (5.1 g, 83% yield): Rƒ = 0.3 (5:95 EtOAc:Hex); Molecular formula: C21H34O4Si; MW: 378.58; IR
(neat) νmax 1737 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.37 – 7.27 (m, 5H), 6.10 (dd, J 17.6, 10.8 Hz, 1H), 5.17 (dd, J
10.8, 0.9 Hz, 1H), 5.08 (dd, J 17.6, 1.0 Hz, 1H), 4.47 (d, J 11.8 Hz, 1H), 4.41 (d, J 11.8 Hz, 1H), 4.24 (dd, J 6.2, 4.8
Hz, 1H), 3.59 (s, 3H), 3.44 (dd, J 10.0, 4.8 Hz, 1H), 3.35 (dd, J 10.0, 6.2 Hz, 1H), 1.26 (s, 3H), 0.84 (s, 9H), 0.04 (s,
13
6H); C NMR (126 MHz, CDCl3) δ 174.9, 139.5, 138.2, 128.4, 127.8, 127.7, 115.0, 75.7, 73.4, 72.8, 53.5, 52.0,
26.0, 18.3, 15.8, -3.9, -4.9 ppm; HRMS calcd for C21H35O4Si [M+H+]: 379.2299, found 379.2301 (0.6 ppm).
Page 15
©ARKAT USA, Inc

Arkivoc 2019, iv, 0-0
Lussier. T. et al.
(±)-(R)-2-[(S)-2-(Benzyloxy)-1-(tert-butyldimethylsilyloxy)ethyl]-2-methylbut-3-en-1-ol
(S1):
Following
General Procedure A and purification by flash chromatography using 10:90 EtOAc:Hex, racemic alcohol S1 (4.5
g, 95% yield) was obtained as a clear oil. 1H NMR and 13C NMR as reported above for enantiopure compound.
(±)-(S)-2-[(S)-2-(Benzyloxy)-1-(tert-butyldimethylsilyloxy)ethyl]-2-methylbut-3-enal (6): Following General
Procedure B and purification by flash chromatography using 20:80 EtOAc:Hex, racemic aldehyde 6 (4.4 g, 97%
yield) was obtained as a clear oil. 1H NMR and 13C NMR as reported above for enantiopure compound.
(±)-(2R,3R)-3-[(S)-2-(Benzyloxy)-1-(tert-butyldimethylsilyloxy)ethyl]-2-hydroxy-3-methylpent-4-enenitrile
(5a) and (±)-(2S,3R)-3-[(S)-2-(benzyloxy)-1-(tert-butyldimethylsilyloxy)ethyl]-2-hydroxy-3-methylpent-4-ene-
1
nitrile (5b): Cyanohydrins 5a and 5b were prepared following General Procedure C. H NMR spectroscopic
analysis of the crude reaction indicated a 6:1 mixture of 2,4-syn and anti diastereomers (Table 1, entry 1).
Purification by flash chromatography using 10:90 EtOAc:Hex provided 5a and 5b as a clear oil (69.1 mg, 79%
yield). 5a: Rƒ = 0.15 (10:90 EtOAc:Hex); Molecular formula: C21H33NO3Si; MW: 375.58; IR (neat) νmax 3447,
1
2362 cm-1; H NMR (500 MHz, CDCl3) δ 7.40 – 7.29 (m, 5H), 6.02 (dd, J 17.6, 11.0 Hz, 1H), 5.34 (dd, J 11.0, 0.9
Hz, 1H), 5.27 (dd, J 17.6, 0.9 Hz, 1H), 4.58 (d, J 4.8 Hz, 1H), 4.55 (d, J 11.7 Hz, 1H), 4.51 (d, J 11.7 Hz, 1H), 4.15
(d, J 5.3 Hz, 1H), 3.87 (dd, J 5.3, 3.9 Hz, 1H), 3.55 (dd, J 10.4, 5.2 Hz, 1H), 3.47 (dd, J 10.4, 3.9 Hz, 1H), 1.20 (s,
13
3H), 0.88 (s, 9H), 0.09 (s, 3H), 0.03 (s, 3H) ppm; C NMR (126 MHz, CDCl3) δ 137.7, 136.8, 128.7, 128.3, 128.1,
118.8, 118.2, 76.1, 73.8, 71.4, 66.7, 49.1, 26.0, 18.3, 17.0, -4.1, -4.9 ppm; HRMS calcd for C21H34O3NSi [M+H+]:
376.2302, found 376.2303 (0.04 ppm). 5b: Rƒ = 0.19 (10:90 EtOAc:Hex); IR (neat) νmax 3424, 2247 cm-1; 1H NMR
(500 MHz, CDCl3) δ 7.39 – 7.27 (m, 5H), 5.89 (dd, J 17.6, 11.0 Hz, 1H), 5.32 (d, J 11.0 Hz, 1H), 5.27 (d, J 17.6 Hz,
1H), 4.70 (d, J 5.7 Hz, 1H), 4.48 (s, 2H), 3.95 (dd, J 4.9, 3.9 Hz, 1H), 3.81 (d, J 6.5 Hz, 1H), 3.55 (dd, J 10.3, 3.9 Hz,
13
1H), 3.43 (dd, J 10.4, 5.0 Hz, 1H), 1.27 (s, 3H), 0.89 (s, 9H), 0.13 (s, 3H), 0.08 (s, 3H); C NMR (126 MHz, CDCl3)
δ 137.6, 137.1, 128.6, 128.0, 127.9, 118.9, 118.2, 77.4, 73.5, 72.3, 68.0, 47.6, 26.0, 18.3, 16.5, -4.1, -4.9 ppm;
HRMS calcd for C21H34O3NSi [M+H+] : 376.2302, found 376.2302 (-0.2 ppm).
(±)-(S)-Methyl 2-[(S)-1,2-bis(benzyloxy)ethyl]-2-methylbut-3-enoate (S3): To a solution of (S)-methyl 2-[(S)-2-
(benzyloxy)-1-hydroxyethyl]-2-methylbut-3-enoate22 (0.32 g, 1.2 mmol, 1.0 equiv.) in a mixture of 2:1
cyclohexane:DCM (6.1 mL, 0.20 M) at 0 oC, benzyl-2,2,2-trichloroacetimidate (340 µL, 1.80 mmol, 1.80 equiv.)
o
and triflic acid (11 µL, 0.12 mmol, 0.10 equiv.) were added. The solution was stirred overnight at 0 C.
Triethylamine (100 µL, 0.61 mmol, 0.50 equiv.) was added and the reaction mixture was then concentrated.
Purification by flash chromatography using 15:85 (EtOAc:Hex): provided protected ester S3 as a clear oil (0.36
g, 84% yield): Rƒ = 0.28 (15:85 EtOAc:Hex); Molecular formula: C22H26O4; MW: 354.45; IR (neat) νmax 3030,
1
2949, 2865, 1734, 1117 cm-1; H NMR (500 MHz, CDCl3) δ 7.48 – 7.06 (m, 10H), 6.15 (dd, J 17.6, 10.9 Hz, 1H),
5.16 (d, J 10.8 Hz, 1H), 5.09 (d, J 17.6 Hz, 1H), 4.76 (d, J 11.5 Hz, 1H), 4.57 (d, J 11.5 Hz, 1H), 4.47 (d, J 11.9 Hz,
1H), 4.43 (d, J 11.9 Hz, 1H), 4.03 (dd, J 6.0, 4.6 Hz, 1H), 3.57 (s, 3H), 3.54 (d, J = 6.1 Hz, 1H), 3.53 (d, J 4.5 Hz,
1H), 1.28 (s, 3H) ppm; 13C NMR (126 MHz, CDCl3) δ 174.9, 138.9, 138.6, 138.3, 128.5, 128.3, 127.72, 127.71,
127.65, 127.5, 115.2, 82.8, 74.2, 73.5, 71.8, 52.9, 52.2, 16.8 ppm; HRMS calcd for C22H27O4 [M+H+]: 355.1904,
found: 355.1912 (2.4 ppm).
(±)-(R)-2-[(S)-1,2-Bis(benzyloxy)ethyl]-2-methylbut-3-en-1-ol (S4): Following General Procedure A and
purification by flash chromatography using 25:75 EtOAc:Hex, provided primary alcohol S4 as a clear oil (58.3
mg, 98% yield): Rƒ = 0.23 (20:80 EtOAc:Hex); Molecular formula: C21H26O3; MW: 326.44; IR (neat) υmax 3443,
1
2871, 1091 cm-1; H NMR (500 MHz, CDCl3) δ 7.39 – 7.26 (m, 10H), 5.98 (dd, J 17.7, 11.0 Hz, 1H), 5.15 (dd, J
11.0, 1.3 Hz, 1H), 5.09 (dd, J 17.8, 1.2 Hz, 1H), 4.83 (d, J 11.5 Hz, 1H), 4.58 (d, J 11.5 Hz, 1H), 4.53 (s, 2H), 3.71
(app.q, J 5.9 Hz, 1H), 3.61 (app.q, J 5.9 Hz, 2H), 3.59 – 3.55 (m, 1H), 3.51 (dd, J 10.9, 5.5 Hz, 1H), 2.46 – 2.41 (m,
1H), 1.08 (s, 3H) ppm; 13C NMR (126 MHz, CDCl3) δ 140.6, 138.6, 138.2, 128.57, 128.53, 128.0, 127.84, 127.82,
Page 16
©ARKAT USA, Inc

Arkivoc 2019, iv, 0-0
Lussier. T. et al.
127.76, 115.0, 83.7, 73.6, 73.6, 71.8, 68.8, 45.5, 18.8 ppm; HRMS calcd for C21H26O3Na [M+Na+]: 349.1774,
found: 349.1781 (1.9 ppm).
(±)-(S)-2-[(S)-1,2-Bis(benzyloxy)ethyl]-2-methylbut-3-enal (17): Following General Procedure B and
purification by flash chromatography using 20:80 EtOAc:Hex, provided aldehyde 17 as a clear oil (1.82 g, 98%
yield): Rƒ = 0.41 (30:70 EtOAc:Hex); Molecular formula: C21H24O3; MW: 324.42; IR (neat) νmax 2865, 1725, 1095
1
cm-1; H NMR (500 MHz, CDCl3) δ 9.54 (s, 1H), 7.38 – 7.27 (m, 10H), 6.10 (dd, J 17.8, 10.9 Hz, 1H), 5.32 (dd, J
10.9, 0.8 Hz, 1H), 5.16 (dd, J 17.8, 0.8 Hz, 1H), 4.77 (d, J 11.5 Hz, 1H), 4.58 (d, J 11.5 Hz, 1H), 4.49 (s, 2H), 3.88
13
(t, J 4.9 Hz, 1H), 3.61 (app.s, 1H), 3.60 (app.s, 1H), 1.20 (s, 3H); C NMR (126 MHz, CDCl3) δ 201.8, 138.4,
138.0, 136.8, 128.6, 128.4, 127.90, 127.86, 127.8 (one aromatic carbon missing), 117.7, 81.8, 73.7, 73.6, 70.4,
56.3, 15.4 ppm; HRMS calcd for C21H24O3Na [M+Na+] : 347.1618, found: 347.1619 (0.4 ppm).
(±)-(2R,3R)-3-[(S)-1,2-Bis(benzyloxy)ethyl]-2-hydroxy-3-methylpent-4-enenitrile (18a) and (±)-(2S,3R)-3-[(S)-
1,2-bis(benzyloxy)ethyl]-2-hydroxy-3-methylpent-4-enenitrile (18b): Cyanohydrins 18a and 18b were
1
prepared following General Procedure C. H NMR spectroscopic analysis of the crude reaction indicated an 8:1
mixture of 2,4-syn and anti diastereomers (Table 1, entry 3). Purification by flash chromatography using 20:80
EtOAc:Hex, provided 18a and 18b (44.2 mg, 92% yield) as a clear oil. 18a: Rƒ = 0.22 (20:80 EtOAc:Hex);
Molecular formula: C22H25NO3; MW: 351.45; IR (neat) νmax 3419, 2244 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.39 –
7.28 (m, 10H), 6.04 (dd, J 17.6, 11.0 Hz, 1H), 5.36 (d, J 11.0 Hz, 1H), 5.28 (d, J 17.6 Hz, 1H), 4.76 (d, J 11.3 Hz,
1H), 4.62 (d, J 4.9 Hz, 1H), 4.56 (d, J 11.9 Hz, 1H), 4.53 (d, J 11.3 Hz, 1H), 4.52 (d, J 11.8 Hz, 1H), 3.78 (d, J 5.0 Hz,
13
1H), 3.72 – 3.65 (m, 2H), 3.60 (dd, J 10.2, 4.0 Hz, 1H), 1.23 (s, 3H) ppm; C NMR (126 MHz, CDCl3) δ 137.8,
137.2, 136.9, 128.7, 128.6, 128.3, 128.13, 128.12, 128.0, 118.57, 118.53, 82.6, 73.8, 73.5, 69.8, 67.2, 48.5, 17.1
ppm; HRMS calcd for C22H25O3NNa [M+Na+]: 374.1727, found 374.1730 (0.8 ppm). 18b: Rƒ = 0.18 (20:80
1
EtOAc:Hex); IR (neat) νmax 3420, 2244 cm-1; H NMR (500 MHz, CDCl3) δ 7.41 – 7.28 (m, 10H), 6.02 (dd, J 17.6,
11.0 Hz, 1H), 5.31 (d, J 11.0 Hz, 1H), 5.24 (d, J 17.7 Hz, 1H), 4.89 (d, J 11.1 Hz, 1H), 4.65 (d, J 11.1 Hz, 1H), 4.53
(s, 2H), 4.40 (d, J 8.8 Hz, 1H), 3.96 (dd, J 5.6, 3.3 Hz, 1H), 3.80 (d, J 8.8 Hz, 1H), 3.63 (dd, J 10.8, 3.3 Hz, 1H), 3.59
(dd, J 10.8, 5.6 Hz, 1H), 1.22 (s, 3H) ppm; 13C NMR (126 MHz, CDCl3) δ 137.8, 137.6, 136.0, 128.9, 128.7, 128.5,
128.4, 128.0, 127.8, 118.9, 118.0, 83.1, 73.9, 73.6, 71.6, 69.4, 47.0, 17.2 ppm; HRMS calcd for C22H25O3NNa
[M+Na+]: 374.1727, found 374.1730 (0.9 ppm).
(±)-(S)-Methyl 2 [(S)-2-(benzyloxy)-1-(4-methoxybenzyloxy)ethyl]-2-methylbut-3-enoate (S5): To a solution
of (S)-methyl 2-[(S)-2-(benzyloxy)-1-hydroxyethyl]-2-methylbut-3-enoate22 (2.0 g, 7.7 mmol, 1.0 equiv.) in dry
o
ether (77 mL, 0.10 M) at 0 C, 4-methoxybenzyl-2,2,2-trichloroacetimidate (6.5 g, 23 mmol, 3.0 equiv.) and
triflic acid (3.4 µL, 0.039 mmol, 0.0050 equiv.) were added. The solution was stirred until the alcohol was all
consumed, 1h30 at 0 oC, as determined by TLC. Triethylamine (11 µL, 0.080 mmol, 0.010 equiv.) was added to
the reaction at 0 oC. An aqueous solution of NaHCO3 was added and the aqueous layer was extracted with
Et2O (3x). The organic layers were combined, dried over MgSO4, filtered and concentrated in vacuo.
Purification by flash chromatography using 20:80 EtOAc:Hex provided protected ester S5 as a clear oil (2.09 g,
70% yield): Rƒ = 0.25 (20:80 EtOAc:Hex); Molecular formula: C23H28O5; MW: 384.47; IR (neat) νmax 1734 cm-1;
1H NMR (500 MHz, CDCl3) δ 7.39 – 7.27 (m, 5H), 7.23 (d, J 8.5 Hz, 2H), 6.86 (d, J 8.6 Hz, 2H), 6.17 (dd, J 17.6,
10.8 Hz, 1H), 5.20 (d, J 10.8 Hz, 1H), 5.13 (d, J 17.6 Hz, 1H), 4.72 (d, J 11.0 Hz, 1H), 4.55 (d, J 11.0 Hz, 1H), 4.52
(d, J 11.9 Hz, 1H), 4.48 (d, J 11.6 Hz, 1H), 4.05 (dd, J 5.9, 4.7 Hz, 1H), 3.80 (s, 3H), 3.62 (s, 3H), 3.60 – 3.53 (m,
13
2H), 1.32 (s, 3H); C NMR (126 MHz, CDCl3) δ 174.9, 159.2, 138.7, 138.3, 131.0, 129.3, 128.5, 127.7, 115.2,
113.7, 82.4, 73.9, 73.5, 71.8, 55.38, 55.36, 52.9, 52.1, 16.7 ppm; HRMS calcd for C23H28O5Na [M+Na+]:
407.1829, found 407.1837 (1.9 ppm).
(±)-(R)-2-[(S)-2-(Benzyloxy)-1-(4-methoxybenzyloxy)ethyl]-2-methylbut-3-en-1-ol (S6): Following General
Procedure A and purification by flash chromatography using 20:80 EtOAc:Hex, provided primary alcohol S6 as
Page 17
©ARKAT USA, Inc

Arkivoc 2019, iv, 0-0
Lussier. T. et al.
a clear oil (1.1 g, quantitative yield): Rƒ = 0.2 (30:70 EtOAc:Hex); Molecular formula: C22H28O4; MW: 356.46; IR
1
(neat) νmax 3451 cm-1; H NMR (500 MHz, CDCl3) δ 7.41 – 7.28 (m, 5H), 7.27 (d, J 8.7 Hz, 2H), 6.88 (d, J 8.6 Hz,
2H), 5.97 (dd, J 17.7, 11.0 Hz, 1H), 5.14 (dd, J 11.0, 1.3 Hz, 1H), 5.08 (dd, J 17.7, 1.3 Hz, 1H), 4.76 (d, J 11.2 Hz,
1H), 4.54 (s, 2H), 4.52 (d, J = 11.1 Hz, 1H), 3.81 (s, 3H), 3.72 – 3.67 (m, 1H), 3.63 – 3.53 (m, 3H), 3.48 (dd, J 11.0,
13
5.5 Hz, 1H), 2.49 (dd, J 7.2, 5.5 Hz, 1H), 1.06 (s, 3H) ppm; C NMR (126 MHz, CDCl3) δ 159.4, 140.6, 138.2,
130.6, 129.7, 128.6, 127.8, 127.7, 114.9, 113.9, 83.3, 73.5, 73.2, 71.9, 68.9, 55.4, 45.4, 18.8 ppm; HRMS calcd
for C22H28O4Na [M+Na+]: 379.1880, found 379.1887 (1.8 ppm).
(±)-(S)-2-[(S)-2-(Benzyloxy)-1-(4-methoxybenzyloxy)ethyl]-2-methylbut-3-enal (19): Following General
Procedure B and purification by flash chromatography using 15:85 EtOAc:Hex provided aldehyde 19 as a clear
oil (1.02 g, 94% yield): Rƒ = 0.2 (30:70 EtOAc:Hex); Molecular formula: C22H26O4; MW: 354.45; IR (neat) νmax
1726 cm-1; 1H NMR (500 MHz, CDCl3) δ 9.55 (s, 1H), 7.41 – 7.29 (m, 5H), 7.25 (d, J 8.5 Hz, 2H), 6.89 (d, J 8.5 Hz,
2H), 6.11 (dd, J 17.8, 10.9 Hz, 1H), 5.33 (d, J 10.9 Hz, 1H), 5.18 (d, J 17.7 Hz, 1H), 4.72 (d, J 11.2 Hz, 1H), 4.54 (d,
J 11.3 Hz, 1H), 4.52 (s, 2H), 3.89 (t, J 4.9 Hz, 1H), 3.82 (s, 3H), 3.62 (d, J 4.9 Hz, 2H), 1.22 (s, 3H); 13C NMR (126
MHz, CDCl3) δ 201.8, 159.3, 137.9, 136.5, 130.3, 129.6, 128.5, 127.8, 127.7, 117.5, 113.8, 81.2, 73.4, 73.2, 70.3,
56.2, 55.3, 15.3 ppm; HRMS calcd for C22H26O4Na [M+Na+]: 377.1723, found 377.1726 (0.7 ppm).
(±)-(2R,3R)-3-[(S)-2-(Benzyloxy)-1-(4-methoxybenzyloxy)ethyl)-2-hydroxy-3-methylpent-4-enenitrile
(20a)
and (±)-(2S,3R)-3-[(S)-2-(benzyloxy)-1-(4-methoxybenzyloxy)ethyl]-2-hydroxy-3-methylpent-4-enenitrile
(20b): Cyanohydrins 20a and 20b were prepared following General Procedure C. 1H NMR spectroscopic
analysis of the crude reaction indicated an 8:1 mixture of 2,4-syn and anti diastereomers (Table 1, entry 4).
Purification by flash chromatography using 25:75 EtOAc:Hex provided 20a and 20b (47.9 mg, 93% yield) as a
clear oil. 20a: Rƒ = 0.13 (25:75 EtOAc:Hex); Molecular formula: C23H27NO4; MW: 381.47; IR (neat) νmax 3431,
1
2247 cm-1; H NMR (500 MHz, CDCl3) δ 7.40 – 7.30 (m, 5H), 7.23 (d, J 8.7 Hz, 2H), 6.87 (d, J 8.7 Hz, 2H), 6.03
(dd, J 17.6, 11.0 Hz, 1H), 5.35 (dd, J 11.0, 0.9 Hz, 1H), 5.27 (dd, J 17.6, 0.9 Hz, 1H), 4.68 (d, J 11.0 Hz, 1H), 4.58
(d, J 5.0 Hz, 1H), 4.55 (s, 1H), 4.54 (s, 1H), 4.46 (d, J 11.0 Hz, 1H), 3.84 (d, J 5.0 Hz, 1H), 3.81 (s, 3H), 3.69 – 3.64
(m, 2H), 3.61 – 3.56 (m, 1H), 1.20 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 159.6, 137.3, 136.9, 129.9, 129.8, 128.7,
128.2, 128.0, 118.6, 118.5, 114.0, 82.3, 73.8, 73.2, 69.9, 67.4, 55.4, 48.4, 17.2 ppm; HRMS calcd for
C23H27NO4Na [M+Na+]: 404.1832, found 404.1826 (-1.5 ppm). 20b: Rƒ = 0.17 (25:75 EtOAc:Hex); IR (neat) νmax
1
3421, 2244 cm-1; H NMR (500 MHz, CDCl3) δ 7.41 – 7.30 (m, 5H), 7.29 (d, J 8.5 Hz, 2H), 6.89 (d, J 8.6 Hz, 2H),
6.01 (dd, J 17.6, 11.0 Hz, 1H), 5.30 (d, J 11.0 Hz, 1H), 5.23 (d, J 17.6 Hz, 1H), 4.82 (d, J 10.8 Hz, 1H), 4.58 (d, J
10.8 Hz, 1H), 4.54 (s, 2H), 4.38 (app.dd, J 8.8, 2.1 Hz, 1H), 3.95 (dd, J 5.7, 3.3 Hz, 1H), 3.92 (app.dd, J 8.8, 2.8 Hz,
13
1H), 3.81 (s, 3H), 3.62 (dd, J 10.8, 3.4 Hz, 1H), 3.58 (dd, J 10.8, 5.6 Hz, 1H), 1.21 (s, 3H) ppm; C NMR (100.6
MHz, CDCl3) δ 159.7, 137.9, 136.0, 130.3, 129.6, 128.6, 128.0, 127.7, 119.0, 117.9, 114.2, 82.8, 73.6, 73.5, 71.7,
69.5, 55.4, 46.9, 17.3 ppm; HRMS calcd for C23H27NO4Na [M+Na+]: 404.1832, found 404.1827 (-1.2 ppm).
(±)-(S)-2-[(S)-2-(Benzyloxy)-1-hydroxyethyl]-2-methylbut-3-enal (21): To a solution of racemic aldehyde 6
o
(0.14 g, 0.42 mmol. 1.0 equiv.) in dry THF (4.1 µL, 0.10 M) at 0 C, HF-pyridine (0.84 mL, 0.84 mmol, 2.0
mL/mmol) was added. The solution was warmed to room temperature and stirred overnight. An aqueous
solution of NaHCO3 was added and the aqueous layer was extracted with Et2O (3x). The organic layers were
combined, dried with MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography using
30:70 EtOAc:Hex provided aldehyde 21 as a clear oil (56.6 mg, 58% yield): Rƒ = 0.23 (30:70 EtOAc:Hex);
Molecular formula: C14H18O3; MW: 234.30; IR (neat) νmax 3460, 1725 cm-1; 1H NMR (500 MHz, CDCl3) δ 9.53 (s,
1H), 7.38 – 7.28 (m, 5H), 6.07 (dd, J 17.7, 10.9 Hz, 1H), 5.39 (d, J 10.9 Hz, 1H), 5.21 (d, J 17.8 Hz, 1H), 4.53 (s,
2H), 4.08 (dd, J 7.3, 3.7 Hz, 1H), 3.54 (dd, J 9.8, 3.7 Hz, 1H), 3.48 (dd, J 9.8, 7.4 Hz, 1H), 2.63 (s, 1H), 1.21 (s, 3H)
ppm; 13C NMR (100.6 MHz, CDCl3) δ 202.3, 137.7, 135.5, 128.5, 127.9, 127.8, 118.4, 73.8, 73.5, 70.7, 55.7,
15.1 ppm; HRMS for C14H18O3Na [M+Na+]: 257.1148, found 257.1146 (-0.9 ppm).
Page 18
©ARKAT USA, Inc

Arkivoc 2019, iv, 0-0
Lussier. T. et al.
(±)-(2R,3R)-3-[(S)-2-(Benzyloxy)-1-hydroxyethyl]-2-hydroxy-3-methylpent-4-enenitrile (22a) and (±)-(2S,3R)-
3-((S)-2-(benzyloxy)-1-hydroxyethyl)-2-hydroxy-3-methylpent-4-enenitrile (22b): Cyanohydrins 22a and 22b
1
were prepared following General Procedure C. H NMR spectroscopic analysis of the crude reaction indicated
a 1:4 mixture of 2,4-syn and anti diastereomers (Table 1, entry 5). Purification by flash chromatography using
50:50 EtOAc:Hex provided 22a and 22b (26 mg, 89% yield). 22a: Rƒ = 0.33 (50:50 EtOAc:Hex); Molecular
1
formula: C15H19NO3; MW: 261.32; IR (neat) νmax 3428, 2246 cm-1; H NMR (500 MHz, CDCl3) δ 7.41 – 7.29 (m,
5H), 6.11 (dd, J 17.7, 11.0 Hz, 1H), 5.43 (dd, J 11.0, 0.8 Hz, 1H), 5.30 (dd, J 17.7, 0.9 Hz, 1H), 4.66 (d, J 4.5 Hz,
1H), 4.57 (d, J 11.7 Hz, 1H), 4.54 (d, J 11.7 Hz, 1H), 3.97 (ddd, J 8.1, 3.9, 2.3 Hz, 1H), 3.72 (d, J 4.5, 1H), 3.58 (dd,
13
J 9.7, 3.8 Hz, 1H), 3.46 (dd, J 9.7, 8.1 Hz, 1H), 2.76 (d, J 2.3 Hz, 1H), 1.17 (s, 3H) ppm; C NMR (100.6 MHz,
CDCl3) δ 137.2, 135.6, 128.8, 128.4, 128.0, 119.2, 118.2, 75.0, 73.8, 70.4, 68.4, 46.9, 16.1 ppm; HRMS for
C15H20O3N [M+H+]: 262.1438, found 262.1438 (0.3 ppm). 22b: Rƒ = 0.29 (50:50 EtOAc:Hex); IR (neat) υmax 3423,
1
2246 cm-1; H NMR (500 MHz, CDCl3) δ 7.42 – 7.28 (m, 5H), 6.15 (dd, J 17.7, 11.0 Hz, 1H), 5.35 (d, J 11.0 Hz,
1H), 5.25 (dd, J 17.7, 0.8 Hz, 1H), 4.54 (s, 2H), 4.41 (d, J 8.0 Hz, 1H), 4.33 (d, J 9.0 Hz, 1H), 4.22 (dd, J 9.1, 2.9 Hz,
13
1H), 3.53 (dd, J 9.6, 3.0 Hz, 1H), 3.37 (app.t, J 9.3 Hz, 1H), 3.03 (s, 1H), 1.15 (s, 3H) ppm; C NMR (126 MHz,
CDCl3) δ 137.4, 135.7, 128.8, 128.2, 127.9, 118.7, 117.9, 74.6, 73.7, 70.6, 70.5, 45.4, 16.7 ppm; HRMS for
C15H19O3NNa [M+Na+]: 284.1257, found 284.1260 (0.9 ppm).
(±)-(S)-Methyl 2-((S)-2,2,3,3,9,9-hexamethyl-8,8-diphenyl-4,7-dioxa-3,8-disiladecan-5-yl)-2-methylbut-3-en-
oate (S7): To a solution of (S)-methyl 2-((S)-2-((tert-butyldiphenylsilyl)oxy)-1-hydroxyethyl)-2-methylbut-3-
enoate22 (1.0 g, 2.5 mmol, 1.0 equiv.) in anhydrous CH2Cl2 (25 mL, 0.10 M) at 0 oC, 2,6-lutidine (0.59 mL, 5.1
mmol, 2.0 equiv.) and TBSOTf (0.84 mL, 3.5 mmol, 1.4 equiv.) were added. The solution was stirred until the
alcohol was consumed, 4 hours at 0 oC, as determined by TLC. An aqueous solution of NH4Cl was added and
the aqueous layer was extracted with Et2O (3×). The organic layers were combined, dried over MgSO4, filtered
and concentrated in vacuo. Purification by flash chromatography using 5:95 EtOAc:Hex provided protected
ester S7 as a clear oil (1.02 g, 76% yield): Rƒ = 0.35 (5:95 EtOAc:Hex); Molecular formula: C30H46O4Si2; MW:
526.86; IR (neat) νmax 1737 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.68 – 7.62 (m, 4H), 7.45 – 7.35 (m, 6H), 6.09 (dd,
J 17.7, 10.8 Hz, 1H), 5.14 (dd, J 10.8, 1.0 Hz, 1H), 5.04 (dd, J 17.7, 1.1 Hz, 1H), 4.19 (t, J 5.5 Hz, 1H), 3.57 (s, 3H),
3.55-3.59 (m, 1H), 3.47 (dd, J 10.9, 5.2 Hz, 1H), 1.25 (s, 3H), 1.04 (s, 9H), 0.79 (s, 9H), 0.02 (s, 3H), -0.08 (s, 3H);
13C NMR (126 MHz, CDCl3) δ 175.1, 139.2, 135.84, 135.79, 133.4, 133.3, 129.84, 129.82, 127.815, 127.807,
114.9, 77.6, 66.4, 53.8, 52.0, 27.2, 25.9, 19.3, 18.2, 16.3, -3.9, -5.0 ppm; HRMS calcd for C30H47O4Si2 [M+H+]:
527.3007, found 527.3010 (0.6 ppm).
(±)-(R)-2-((S)-2,2,3,3,9,9-Hexamethyl-8,8-diphenyl-4,7-dioxa-3,8-disiladecan-5-yl)-2-methylbut-3-en-1-ol
(S8): Following General Procedure A and purification by flash chromatography using 5:95 EtOAc:Hex, primary
alcohol S8 was obtained as a clear oil (0.73 g, 97% yield): Rƒ = 0.24 (5:95 EtOAc:Hex); Molecular formula:
1
C29H46O3Si2; MW: 498.85; IR (neat) νmax 3454, 2955, 2932, 1111 cm-1; H NMR (500 MHz, CDCl3) δ 7.69 – 7.63
(m, 4H), 7.48 – 7.35 (m, 6H), 5.84 (dd, J 17.7, 11.0 Hz, 1H), 5.05 (dd, J 11.0, 1.3 Hz, 1H), 5.00 (dd, J 17.7, 1.4 Hz,
1H), 3.73 (dd, J 10.9, 5.5 Hz, 1H), 3.67 (dd, J 5.6, 4.2 Hz, 1H), 3.65 – 3.62 (m, 1H), 3.54 (dd, J 10.8, 4.0 Hz, 1H),
3.49 (dd, J 10.9, 6.2 Hz, 1H), 2.65 (t, J 6.3 Hz, 1H), 1.06 (s, 9H), 1.05 (s, 3H), 0.83 (s, 9H), 0.04 (s, 3H), -0.11 (s,
13
3H) ppm; C NMR (126 MHz, CDCl3) δ 141.7, 135.92, 135.85, 133.1, 133.0, 129.952, 129.951, 127.88, 127.85,
114.5, 79.1, 68.3, 66.5, 46.2, 27.0, 26.0, 19.2, 18.247, 18.246, -4.0, -4.9 ppm; HRMS calcd for C29H47O3Si2
[M+H+]: 499.3058, found 499.3062 (0.7 ppm).
(±)-(S)-2-((S)-2,2,3,3,9,9-hexamethyl-8,8-diphenyl-4,7-dioxa-3,8-disiladecan-5-yl)-2-methylbut-3-enal
(23):
Following General Procedure B and purification by flash chromatography using 5:95 EtOAc:Hex provided
aldehyde 21 as a clear oil (0.53 g, 75% yield): Rƒ = 0.30 (5:95 EtOAc:Hex); Molecular formula: C29H44O3Si2; MW:
1
496.84; IR (neat) νmax 1727 cm-1; H NMR (500 MHz, CDCl3) δ 9.68 (s, 1H), 7.38-7.67 (m, 10H), 6.06 (dd, J 10.9,
Page 19
©ARKAT USA, Inc

Arkivoc 2019, iv, 0-0
Lussier. T. et al.
17.6 Hz, 1H), 5.29 (dd, J 0.7, 11.0 Hz, 1H), 5.14 (dd, J 0.7, 17.8 Hz, 1H), 4.01 (dd, J 4.5, 6.5 Hz, 1H), 3.58 (dd, J
6.6, 10.7 Hz, 1H), 3.53 (dd, J 4.5, 10.9 Hz, 1H), 1.20 (s, 3H), 1.04 (s, 9H), 0.81 (s, 9H), 0.01 (s, 3H), -0.15 (s, 3H);
13C NMR (126 MHz, CDCl3) δ 201.7, 137.3, 135.83, 135.79, 133.0, 132.9, 129.96, 129.95, 127.89, 127.87, 117.1,
76.7, 65.5, 56.9, 26.9, 25.9, 19.2, 18.2, 14.4, -4.1, -4.9 ppm; HRMS calcd for C29H44O3Si2Na [M+Na+]: 519.2721,
found 519.2724 (0.5 ppm).
(±)-(2R,3R)-3-((S)-2,2,3,3,9,9-hexamethyl-8,8-diphenyl-4,7-dioxa-3,8-disiladecan-5-yl)-2-hydroxy-3-methyl-
pent-4-enenitrile (24a) and (±)-(2S,3R)-3-((S)-2,2,3,3,9,9-hexamethyl-8,8-diphenyl-4,7-dioxa-3,8-disiladecan-
5-yl)-2-hydroxy-3-methylpent-4-enenitrile (24b): Cyanohydrins 24a and 24b were prepared following General
1
Procedure C. H NMR spectroscopic analysis of the crude reaction indicated a 1.5:1 mixture of 2,4-syn and
anti diastereomers (Table 1, entry 6). Purification by flash chromatography using 25:75 iPr2O:Hex provided 24a
and 24b (67 mg, 93% yield) as clear oils. 24a: Rƒ = 0.29 (25:75 iPr2O:Hex); Molecular formula: C30H45NO3Si2;
1
MW: 523.86; IR (neat) νmax 3448, 2249 cm-1; H NMR (500 MHz, CDCl3) δ 7.72 – 7.62 (m, 4H), 7.52 – 7.36 (m,
6H), 5.98 (dd, J 17.6, 11.0 Hz, 1H), 5.30 (dd, J 10.9, 0.9 Hz, 1H), 5.23 (dd, J 17.6, 0.9 Hz, 1H), 4.53 (d, J 6.6 Hz,
1H), 4.25 (d, J 6.6 Hz, 1H), 3.87 (dd, J 6.9, 3.6 Hz, 1H), 3.64 (dd, J 11.3, 6.9 Hz, 1H), 3.52 (dd, J 11.3, 3.6 Hz, 1H),
1.16 (s, 3H), 1.08 (s, 9H), 0.78 (s, 9H), 0.01 (s, 3H), -0.25 (s,3H) ppm; 13C NMR (126 MHz, CDCl3) δ 138.4, 135.90,
135.88, 132.13, 132.09, 130.34, 130.30, 128.11, 128.08, 118.8, 118.0, 76.7, 67.1, 65.6, 49.5, 27.0, 26.0, 19.2,
18.2, 15.3, -4.2, -5.0 ppm; HRMS calcd for C30H46NO3Si2 [M+H+]: 524.3011, found 524.3011 (0.07 ppm). 24b : Rƒ
= 0.21 (25:75 iPr2O:Hex); IR (neat) νmax 3423, 2247 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.67 – 7.61 (m, 4H), 7.49 –
7.35 (m, 6H), 5.83 (dd, J 17.6, 11.0 Hz, 1H), 5.28 (dd, J 10.9, 0.8 Hz, 1H), 5.22 (dd, J 17.6, 0.8 Hz, 1H), 4.77 (d, J
6.2 Hz, 1H), 3.83 (dd, J 5.5, 3.9 Hz, 1H), 3.79 (d, J 6.2 Hz, 1H), 3.66 (dd, J 11.3, 5.5 Hz, 1H), 3.58 (dd, J 11.3, 3.9
13
Hz, 1H), 1.22 (s, 3H), 1.07 (s, 9H), 0.84 (s, 9H), 0.09 (s, 3H), -0.09 (s, 3H) ppm; C NMR (126 MHz, CDCl3) δ
137.0, 135.93, 135.85, 132.8, 132.7, 130.13, 130.12, 128.00, 127.95, 118.9, 118.4, 78.4, 68.2, 66.0, 47.9, 27.0,
26.0, 19.2, 18.2, 16.2, -4.2, -5.0 ppm; HRMS calcd for C30H46NO3Si2 [M+H+]: 524.3011, found 524.3007 (-0.8
ppm).
(±)-(R)-Methyl 3-hydroxy-2,2-dimethyl-6-phenylhexanoate (S9): To a solution of 4-phenylbutanal43 (2.4 g, 16
mmol, 1.0 equiv.) in anhydrous CH2Cl2 (160 ml, 0.10 M) at –40 oC, BF3·OEt2 (3.0 ml, 24 mmol, 1.5 equiv.) was
added. A solution of the commercially available enoxysilane ((1-methoxy-2-methylprop-1-en-1-
yl)oxy)trimethylsilane) (6.5 ml, 32 mmol, 2.0 equiv.) in CH2Cl2 was immediately added at the same
temperature. The resulting solution was stirred until the aldehyde was completely consumed as indicated by
TLC (one hour). A saturated aqueous solution of NH4Cl was added and the aqueous layer was extracted with
Et2O (3×). The organic layers were combined, washed with brine, dried over MgSO4, filtered and concentrated
in vacuo. Purification by flash chromatography using 25:75 EtOAc:Hex provided ester S9 as a clear oil
(quantitative yield after 2 steps, 4.0 g): Rƒ = 0.25 (25:75 EtOAc:Hex); Molecular formula: C15H22O3; MW: 250.34;
1
IR (neat) νmax 3496, 1729 cm-1; H NMR (500 MHz, CDCl3) δ 7.32 – 7.14 (m, 5H), 3.69 (s, 3H), 3.64 (ddd, J 10.6,
6.9, 2.1 Hz, 1H), 2.65 (m, 2H), 2.41 (d, J 6.9 Hz, 1H), 2.04 – 1.88 (m, 1H), 1.75 – 1.61 (m, 1H), 1.49 (m, 1H), 1.39
13
– 1.28 (m, 1H), 1.18 (s, 3H), 1.16 (s, 3H); C NMR (100.6 MHz, CDCl3) δ 178.6, 142.7, 128.7, 128.6, 126.0, 76.8,
52.3, 47.5, 36.0, 31.5, 28.7, 22.7, 20.7; HRMS calcd for C15H22O3Na [M+Na+]: 273.1461, found 273.1458 (-1.1
ppm).
(±)-(R)-Methyl 3-(tert-butyldimethylsilyloxy)-2,2-dimethyl-6-phenylhexanoate (S10): To a solution of
secondary alcohol S9 (0.88 g, 3.5 mmol, 1.0 equiv.) in anhydrous CH2Cl2 (35 mL, 0.10 M) at 0 oC, pyridine (0.56
mL, 7.0 mmol, 2.0 equiv.) and TBSOTf (1.1 mL, 4.9 mmol, 1.4 equiv.) were added. The solution was stirred until
the alcohol was consumed, 2.5 hours at 0 oC, as determined by TLC. An aqueous solution of NH4Cl was added
and the aqueous layer extracted with Et2O (3×). The organic layers were combined, dried over MgSO4, filtered
and concentrated in vacuo. Purification by flash chromatography using 5:95 EtOAc:Hex provided protected
Page 20
©ARKAT USA, Inc

Arkivoc 2019, iv, 0-0
Lussier. T. et al.
ester S10: Rƒ = 0.25 (5:95 EtOAc:Hex); Molecular formula: C21H36O3Si; MW: 364.60; IR (neat) νmax 1735 cm-1; 1H
NMR (500 MHz, CDCl3) δ 7.34 – 7.27 (m, 2H), 7.24 – 7.17 (m, 3H), 3.97 (dd, J 6.5, 4.1 Hz, 1H), 3.65 (s, 3H), 2.72
– 2.52 (m, 2H), 1.90 – 1.78 (m, 1H), 1.68 – 1.56 (m, 1H), 1.55 – 1.42 (m, 2H), 1.22 (s, 3H), 1.13 (s, 3H), 0.94 (s,
13
9H), 0.10 (s, 3H), 0.08 (s, 3H) ppm; C NMR (100.6 MHz, CDCl3) δ 177.8, 142.4, 128.6, 128.5, 126., 77.2, 51.8,
48.6, 36.4, 33.9, 29.1, 26.3, 22.4, 20.2, 18.6, -3.4, -4.0 ppm; HRMS for C21H37O3Si [M+H+]: 365.2506, found
365.2508 (0.4 ppm).
(±)-(R)-3-(tert-Butyldimethylsilyloxy)-2,2-dimethyl-6-phenylhexan-1-ol (S11): Following General Procedure A
and purification by flash chromatography using 10:90 EtOAc:Hex, primary alcohol S11 was obtained as a clear
oil (0.7 g, 60% yield over two steps): Rƒ = 0.2 (10:90 EtOAc:Hex); Molecular formula: C20H36O2Si; MW: 336.59; IR
1
(neat) νmax 3443, 2929, 2857, 1472 cm-1; H NMR (500 MHz, CDCl3) δ 7.31 – 7.25 (m, 2H), 7.22 – 7.11 (m, 3H),
3.71 (dd, J 10.8, 3.0 Hz, 1H), 3.51 (dd, J 6.0, 3.8 Hz, 1H), 3.25 (dd, J 10.7, 7.6 Hz, 1H), 2.86 (dd, J 7.6, 3.1 Hz, 1H),
2.68 – 2.54 (m, 2H), 1.90 – 1.80 (m, 1H), 1.79 – 1.65 (m, 1H), 1.67 – 1.59 (m, 1H), 1.58 – 1.47 (m, 1H), 1.03 (s,
13
3H), 0.91 (s, 9H), 0.77 (s, 3H), 0.10 (s, 3H), 0.05 (s, 3H) ppm; C NMR (100.6 MHz, CDCl3) δ 142.3, 128.5, 128.4,
125.9, 80.9, 70.4, 39.5, 36.5, 33.3, 29.4, 26.2, 23.9, 21.9, 18.3, -3.7, -4.1 ppm; HRMS for
C20H37O2Si [M+H+]: 337.2557, found 337.2561 (1.0 ppm).
(±)-(R)-3-(tert-Butyldimethylsilyloxy)-2,2-dimethyl-6-phenylhexanal (25): Following General Procedure B and
purification by flash chromatography using 5:95 EtOAc:Hex provided aldehyde 25 as a clear oil (0.69 g, 99%
1
yield): Rƒ = 0.21 (5:95 EtOAc:Hex); Molecular formula: C20H34O2Si; MW: 334.58; IR (neat) νmax 1728 cm-1; H
NMR (500 MHz, CDCl3) δ 9.62 (s, 1H), 7.32 – 7.25 (m, 2H), 7.23 – 7.13 (m, 3H), 3.80 – 3.77 (m, 1H), 2.67 – 2.53
(m, 2H), 1.82 – 1.71 (m, 1H), 1.67 – 1.58 (m, 1H), 1.58 – 1.45 (m, 2H), 1.05 (s, 3H), 1.02 (s, 3H), 0.90 (s, 9H),
13
0.06 (s, 3H), 0.05 (s, 3H) ppm; C NMR (100.6 MHz, CDCl3) δ 206.7, 142.0, 128.44, 128.43, 125.9, 76.8, 51.4,
36.3, 33.3, 28.3, 26.0, 19.6, 18.3, 17.9, -3.6, -4.2 ppm; HRMS for C20H33O2Si [M-H+]: 333.2255, found 333.2248
(1.2 ppm).
(±)-(2R,4R)-4-(tert-Butyldimethylsilyloxy)-2-hydroxy-3,3-dimethyl-7-phenylheptanenitrile (26a) and (±)-(2S,-
4R)-4-(tert-butyldimethylsilyloxy)-2-hydroxy-3,3-dimethyl-7-phenylheptanenitrile (26b): Cyanohydrins 26a
1
and 26b were prepared following General Procedure C. H NMR spectroscopic analysis of the crude reaction
indicated a 2.5:1 mixture of 2,4-syn and anti diastereomers (Table 1, entry 7). Purification by flash
chromatography using 5:95 EtOAc:Hex provided 26a and 26b (63 mg, 82% yield) as a clear oil. 26a: Rƒ = 0.28
(15:85 EtOAc:Hex); Molecular formula: C21H35NO2Si; MW: 361.60; IR (neat) νmax 3446, 2246 cm-1; 1H NMR (500
MHz, CDCl3) δ 7.31 – 7.27 (m, 2H), 7.22 – 7.14 (m, 3H), 4.40 (d, J 6.5 Hz, 1H), 3.60 (dd, J 5.7, 3.3 Hz, 1H), 3.34
(d, J 6.4 Hz, 1H), 2.68 – 2.55 (m, 2H), 1.90 – 1.78 (m, 2H), 1.70 – 1.48 (m, 2H), 1.05 (s, 3H), 1.04 (s, 3H), 0.89 (s,
13
9H), 0.11 (s, 3H), 0.06 (s, 3H) ppm; C NMR (100.6 MHz, CDCl3) δ 142.0, 128.5, 126.0, (one aromatic carbon
missing), 119.3, 79.8, 69.2, 42.7, 36.3, 33.6, 29.8, 26.1, 22.0, 19.0, 18.4, -3.7, -4.2 ppm; HRMS for
C21H36O2NSi [M+H+]: 362.2510, found 362.2513 (0.8 ppm). 26b: Rƒ = 0.34 (15:85 EtOAc:Hex); IR (neat) νmax
1
3435, 2245 cm-1; H NMR (500 MHz, CDCl3) δ 7.31 – 7.27 (m, 2H), 7.22 – 7.14 (m, 3H), 4.51 (d, J 4.0 Hz, 1H),
4.24 (d, J 4.1 Hz, 1H), 3.69 (dd, J 5.5, 4.0 Hz, 1H), 2.69 – 2.51 (m, 2H), 1.90 – 1.78 (m, 1H), 1.75 – 1.58 (m, 2H),
13
1.54 – 1.43 (m, 1H), 1.15 (s, 3H), 0.98 (s, 3H), 0.89 (s, 9H), 0.13 (s, 3H), 0.07 (s, 3H) ppm; C NMR (100.6 MHz,
CDCl3) δ 141.7, 128.6, 128.5, 126.2, 119.0, 80.3, 69.6, 41.7, 36.3, 33.1, 29.4, 26.1, 21.6, 20.7, 18.3, -3.8, -4.2
ppm; HRMS for C21H36O2NSi [M+H+]: 362.2510, found 362.2513 (0.9 ppm).
(±)-(S)-Methyl 4-(benzyloxy)-3-hydroxy-2,2-dimethylbutanoate (S12): To a solution of crude 2-(benzyloxy)-
acetaldehyde44 (1.8 g, 12 mmol, 1.0 equiv.) in anhydrous CH2Cl2 (125 mL, 0.10 M) at –78 oC, TiCl4 (1.00 M, 13.8
mL, 13.8 mmol, 1.15 equiv.) and commercially available enoxysilane ((1-methoxy-2-methylprop-1-en-1-
yl)oxy)trimethylsilane) (4.9 mL, 24 mmol, 2.0 equiv.) were added. The resulting solution was stirred until the
aldehyde was completely consumed as indicated by TLC (generally 90 min). A saturated aqueous solution of
Page 21
©ARKAT USA, Inc

Arkivoc 2019, iv, 0-0
Lussier. T. et al.
NH4Cl was added and the aqueous layer was extracted with EtOAc (3×). The organic layers were combined,
washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification provided S12 (2.22 g,
73%) which has been previously reported in the literature.45
(±)-(S)-Methyl 4-(benzyloxy)-3-(tert-butyldimethylsilyloxy)-2,2-dimethylbutanoate (S13): To a solution of
alcohol S12 (2.2 g, 8.8 mmol, 1.0 equiv.) in anhydrous CH2Cl2 (87 mL, 0.10 M) at 0 oC, 2,6-lutidine (2.0 mL, 18
mmol, 2.0 equiv.) and TBSOTf (2.8 mL, 12 mmol, 1.4 equiv.) were added. The solution was stirred until the
alcohol was all consumed (1h 30m). An aqueous solution of NH4Cl was added and the aqueous layer was
extracted with Et2O (3×). The organic layers were combined, dried over MgSO4, filtered and concentrated in
vacuo. Purification by flash chromatography using 5:95 EtOAc:Hex provided protected ester S13 as a clear oil
(2.7 g, 85% yield): Rƒ = 0.32 (10:90 EtOAc:Hex); Molecular formula: C20H34O4Si; MW: 366.57; IR (neat) νmax
2953, 2857, 1736, 1468 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.37 – 7.24 (m, 5H), 4.48 (d, J 11.8 Hz, 1H), 4.42 (d, J
11.8 Hz, 1H), 4.14 (appt, J 5.6 Hz, 1H), 3.57 (s, 3H), 3.45 (dd, J 9.9, 5.0 Hz, 1H), 3.38 (dd, J 9.9, 6.2 Hz, 1H), 1.18
13
(s, 3H), 1.12 (s, 3H), 0.87 (s, 9H), 0.07 (s, 6H) ppm; C NMR (100.6 MHz, CDCl3) δ 177.2, 138.2, 128.4, 127.8,
127.6, 75.5, 73.4, 72.6, 51.7, 46.7, 26.0, 22.7, 19.4, 18.3, -3.9, -5.0 ppm; HRMS calcd for C20H35O4Si [M+H+]:
367.2299, found 367.2293 (-1.7 ppm).
(±)-(S)-4-(Benzyloxy)-3-(tert-butyldimethylsilyloxy)-2,2-dimethylbutan-1-ol
(S14):
Following
General
Procedure A and purification by flash chromatography using 25:75 EtOAc:Hex, provided alcohol S14 as a clear
oil (2.1 g, 82% yield): Rƒ = 0.32 (25:75 EtOAc:Hex); Molecular formula: C19H34O3Si; MW: 338.56; IR (neat) νmax
3449, 2956, 2930, 2858, 1471, 1095 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.39 – 7.26 (m, 5H), 4.51 (s, 2H), 3.67 (t,
J 4.6 Hz, 1H), 3.63 (dd, J 9.9, 4.6 Hz, 1H), 3.49 – 3.38 (m, 3H), 3.14 (t, J 6.0 Hz, 1H), 0.96 (s, 3H), 0.89 (s, 9H),
13
0.88 (s, 3H), 0.08 (s, 3H), 0.05 (s, 3H); C NMR (100.6 MHz, CDCl3) δ 137.8, 128.5, 127.88, 127.86, 78.5, 73.6,
72.4, 69.9, 39.3, 26.1, 22.5, 22.3, 18.3, -4.0, -4.9 ppm; HRMS calcd for C19H35O3Si [M+H+]: 339.2350, found
339.2347 (-0.8 ppm).
(±)-(S)-4-(Benzyloxy)-3-(tert-butyldimethylsilyloxy)-2,2-dimethylbutanal (27): Following General Procedure B
and purification by flash chromatography using 10:90 EtOAc:Hex provided aldehyde 27 as a clear oil (1.9 g,
91% yield): Rƒ = 0.31 (10:90 EtOAc:Hex); Molecular formula: C19H32O3Si; MW: 336.55 ; IR (neat) νmax 1727 cm-1;
1H NMR (500 MHz, CDCl3) δ 9.59 (s, 1H), 7.37 – 7.26 (m, 5H), 4.47 (d, J 12.2 Hz, 1H), 4.44 (d, J 12.0 Hz, 1H), 3.95
(t, J 5.3 Hz, 1H), 3.45 (dd, J 9.6, 5.1 Hz, 1H), 3.42 (dd, J 9.6, 5.0 Hz, 1H), 1.05 (s, 6H), 0.87 (s, 9H), 0.07 (s, 3H),
0.05 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 205.0, 137.9, 128.5, 127.82, 127.79, 75.5, 73.5, 71.8, 50.1, 26.0, 19.1,
18.3, 17.9, -4.0, -4.9 ppm; HRMS calcd for C19H31O3Si [M-H+]: 335.2048, found 335.2033 (-1.2 ppm).
(±)-(2R,4S)-5-(Benzyloxy)-4-(tert-butyldimethylsilyloxy)-2-hydroxy-3,3-imethylpentanenitrile (28a) and (±)-
(2S,4S)-5-(benzyloxy)-4-(tert-butyldimethylsilyloxy)-2-hydroxy-3,3-dimethylpentanenitrile (28b): Cyano-
1
hydrins 28a and 28b were prepared following General Procedure C. H NMR spectroscopic analysis of the
crude reaction indicated an 11:1 mixture of 2,4-syn and anti diastereomers (Table 1, entry 8). Purification by
flash chromatography using 15:85 EtOAc:Hex provided 28a and 28b (36.9 mg, 79% yield) as a clear oil. 28a: Rƒ
1
= 0.38 (20:80 EtOAc:Hex); Molecular formula: C20H33NO3Si; MW: 363.57; IR (neat) νmax 3442, 2247 cm-1; H
NMR (500 MHz, CDCl3) δ 7.40 – 7.29 (m, 5H), 4.78 (d, J 6.3 Hz, 1H), 4.56 (s, 2H), 4.47 (d, J 5.7 Hz, 1H), 3.74 (dd,
J 6.0, 3.3 Hz, 1H), 3.57 (dd, J 10.5, 6.1 Hz, 1H), 3.50 (dd, J 10.5, 3.3 Hz, 1H), 1.09 (s, 3H), 1.07 (s, 3H), 0.88 (s,
13
9H), 0.08 (s, 3H), 0.02 (s, 3H) ppm; C NMR (100.6 MHz, CDCl3) δ 136.5, 128.8, 128.5, 128.2, 119.4, 76.2, 74.0,
70.7, 67.7, 42.9, 25.9, 21.5, 20.9, 18.2, -4.1, -4.9 ppm; HRMS for C20H34O3NSi [M+H+]: 364.2302, found
1
364.2298 (-1.3 ppm). 28b: Rƒ = 0.40 (20:80 EtOAc:Hex); IR (neat) νmax 3433, 2245 cm-1; H NMR (500 MHz,
CDCl3) δ 7.42 – 7.28 (m, 5H), 4.55 (d, J 5.6 Hz, 1H), 4.53 (d, J 12.2 Hz, 1H), 4.50 (d, J 11.9 Hz, 1H), 4.35 (d, J 5.6
Hz, 1H), 3.85 (appt, J 4.2 Hz, 1H), 3.61 (dd, J 10.3, 3.9 Hz, 1H), 3.50 (dd, J 10.3, 4.6 Hz, 1H), 1.17 (s, 3H), 1.03 (s,
3H), 0.90 (s, 9H), 0.13 (s,3H), 0.08 (s, 3H) ppm; 13C NMR (100.6 MHz, CDCl3) δ 137.4, 128.6, 128.1, 127.9, 119.0,
Page 22
©ARKAT USA, Inc

Arkivoc 2019, iv, 0-0
Lussier. T. et al.
78.4, 73.6, 71.6, 69.8, 41.1, 26.0, 21.4, 21.1, 18.3, -4.1, -5.0 ppm; HRMS calcd for C20H34O3NSi [M+H+]:
364.23025, found 364.23016 (-0.2 ppm).
Compounds 4, 29, 30, 31, 32 and 33 from Scheme 7:
(+)-(5S,6S,7R)-5-[(Benzyloxy)methyl]-7-[bis(ethylthio)methyl]-2,2,3,3,6,9,9,10,10-nonamethyl-6-vinyl-4,8-
dioxa-3,9-disilaundecane (4): A solution of cyanohydrin 16 (2.2 g, 4.5 mmol, 1.0 equiv.) in toluene (9.0 mL,
0.50 M) was cooled to 0 oC followed by dropwise addition of DIBAL-H (1.0 M in hexanes, 6.7 mL, 6.7 mmol, 1.4
o
equiv.). After stirring 1 hour at 0 C, saturated aqueous Rochelle salt (15 mL) was added slowly and the
biphasic mixture was warmed to room temperature, diluted with Et2O (10 mL) and stirred vigorously for 2
hours. The aqueous layer was extracted with Et2O (1 × 15 mL) and the combined organic layers dried over
MgSO4, filtered and concentrated in vacuo. The residue was dissolved in EtOAc and 1N HCl (2:1, 30 mL) was
added. The biphasic mixture was stirred vigorously for 1 hour at which point, Et2O was added (15 mL), the
layers separated, and the organic layer extracted with Et2O (1 × 15 mL). The combined organic fractions were
washed with water followed by brine, dried over MgSO4 and concentrated in vacuo to afford the crude
aldehyde (2.2 g, quantitative yield) which was used immediately for the next step. The aldehyde (2.2 g, 4.5
o
mmol, 1.0 equiv.) was dissolved in CH2Cl2 (22 mL, 0.20 M) and the resulting solution was cooled to -78 C
followed by addition of ethanethiol (1.0 mL, 14 mmol, 3.2 equiv.) and BF3·OEt2 (0.72 mL, 5.8 mmol, 1.3 equiv.).
The resulting reaction mixture was stirred 4 hours at -78 oC before Et3N (3.1 mL, 23 mL, 5.0 equiv.) was added
dropwise with stirring for an additional 20 minutes. Saturated aqueous NaHCO3 (25 mL) was added slowly and
the biphasic mixture warmed to room temperature. After stirring vigorously for 30 minutes, the layers were
separated, and the aqueous layer extracted with hexanes (2 × 20 mL). The combined organic fractions were
washed with 1N NaOH (2 × 15 mL, to remove excess EtSH), water and brine, dried over MgSO4, filtered and
concentrated in vacuo. Purification by flash chromatography (Hexanes/DCM) provided the pure dithioacetal 4
[]25
as a slightly yellow oil (1.9 g, 70% yield): Rf = 0.45 (Hexanes/ DCM 70:30);
+3.6 (c=1.6, CH2Cl2); Molecular
D
formula: C31H58O3S2Si2; MW: 599.09; IR (neat) νmax 2954, 2927, 2854, 1089 cm-1; H NMR (500 MHz, CDCl3) δ
7.35 – 7.26 (m, 5H), 6.04 (dd, J 17.6, 10.9 Hz, 1H), 5.10 (dd, J 10.9, 0.9 Hz, 1H), 4.99 (dd, J 17.6, 1.0 Hz, 1H),
4.49 (d, J 11.9 Hz, 1H), 4.45 (d, J 11.9 Hz, 1H), 4.12 (dd, J 7.4, 1.0 Hz, 1H), 3.99 – 3.88 (m, 3H), 3.31 (dd, J 9.5,
7.6 Hz, 1H), 2.73 – 2.55 (m, 2H), 2.49 (q, J 7.4 Hz, 2H), 1.23 (td, J 7.4, 3.5 Hz, 6H), 1.05 (s, 3H), 0.92 (s, 9H), 0.84
1
13
(s, 9H), 0.24 (s, 3H), 0.10 (s, 3H), 0.02 (s, 3H), 0.02 (s, 3H) ppm; C NMR (126 MHz, CDCl3) δ 143.9, 138.7,
128.3, 127.9, 127.4, 114.3, 82.6, 75.3, 73.6, 73.4, 54.7, 50.6, 27.0, 26.61, 26.58, 26.3, 19.0, 18.6, 15.9, 14.6,
14.4, -2.3, -3.5, -4.4, -4.7 ppm; HRMS calcd for C31H58O3S2Si2Na [M+Na+]: 621.3258; found 621.3240 (-3.0 ppm).
(–)-1-((2R,3R,4S)-4-{(S)-2-(Benzyloxy)-1-[(tert-butyldimethylsilyl)oxy]ethyl}-3-[(tert-butyldimethylsilyl)oxy]-
2-(ethylthio)-4-methylhex-5-en-1-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (29): To a solution of dithioacetal
4 (60 mg, 0.10 mmol, 1.0 equiv.) in THF (0.50 mL, 0.20 M) at 0 oC, silylated thymine (0.50 M in DCE, 0.40 mL,
0.20 mmol, 2.0 equiv.) and iodine (51 mg, 0.20 mmol, 2.0 equiv.) were added. The resulting dark purple
reaction mixture was stirred 16 hours at 0 oC before addition of saturated aqueous Na2S2O3 (2 mL) followed by
addition of a few drops of 2N NaOH. The biphasic mixture was warmed to room temperature and stirred
vigorously until a clear homogeneous biphasic mixture was obtained. The aqueous layer was extracted with
Et2O (2 × 2 mL) and the combined organic fractions were washed with brine, dried over MgSO4, filtered and
1
concentrated in vacuo. H NMR spectroscopic analysis of the unpurified product indicated the formation of
only one diastereomer. Purification by flash chromatography provided thioaminal 29 as a white foam (44 mg,
[]2D5
66% yield): Rf = 0.54 (Hexanes/EtOAc, 70:30);
-11 (c= 1.9, CH2Cl2); Molecular formula: C34H58N2O5SSi2;
MW: 663.08; IR (neat) νmax 2927, 2855, 1676, 1089 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.02 (s, 1H), 7.63 (d, J 1.2
Hz, 1H), 7.35 – 7.28 (m, 5H), 6.01 – 5.94 (m, 2H), 5.17 (dd, J 10.9, 1.3 Hz, 1H), 5.06 (dd, J 17.7, 1.3 Hz, 1H), 4.45
(d, J 11.7 Hz, 1H), 4.41 (d, J 11.6 Hz, 1H), 4.23 (d, J 2.1 Hz, 1H), 4.13 (dd, J 7.0, 3.7 Hz, 1H), 3.55 (dd, J 10.0, 3.7
Page 23
©ARKAT USA, Inc

Arkivoc 2019, iv, 0-0
Lussier. T. et al.
Hz, 1H), 3.31 (dd, J 10.0, 7.0 Hz, 1H), 2.41 – 2.24 (m, 2H), 1.93 (d, J 1.2 Hz, 3H), 1.21 (t, J 7.4 Hz, 3H), 1.11 (s,
13
3H), 0.97 (s, 9H), 0.79 (s, 9H), 0.12 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H), -0.01 (s, 3H) ppm; C NMR (126 MHz,
CDCl3) δ 163.6, 150.5, 141.0, 138.3, 138.1, 128.4, 128.0, 127.7, 116.1, 111.2, 79.5, 73.5, 73.4, 73.0, 64.9, 50.5,
26.6, 26.1, 24.3, 19.3, 18.5, 14.3, 13.9, 12.5, -1.8, -3.53, -3.57, -4.5 ppm; HRMS calcd for C34H58N2O5SSi2Na
[M+Na+]: 685.3497; found 685.3487 (-1.4 ppm).
(–)-1-{(1S,2R,3S)-3-[(S)-2-(Benzyloxy)-1-hydroxyethyl]-2-(tert-butyldimethylsilyl)oxy]-1-(ethylthio)-3-methyl-
pent-4-en-1-yl}-5-methylpyrimidine-2,4(1H,3H)-dione (30): To a solution of thioaminal 29 (66 mg, 0.10 mmol,
1.0 equiv.) in DCM/MeOH (1:1, 5 mL, 0.02M), TsOH·H2O (95 mg, 0.50 mmol, 5.0 equiv.) was added. The
o
resulting mixture was warmed to 50 C and stirring was continued for 16 hours. The reaction mixture was
cooled to room temperature and Et3N (84 µL, 0.60 mmol, 6.0 equiv.) was added. After evaporation of the
volatiles, the residue was purified by flash chromatography to afford 30 as a white foam (40 mg, 73% yield): Rf
[]2D5
= 0.47 (Hexanes/EtOAc, 60:40);
-51 (c= 2.0, CH2Cl2); Molecular formula: C28H44N2O5SSi; MW: 548.81; IR
(neat) νmax 3427, 1678 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.87 (s, 1H), 7.77 (d, J 1.2 Hz, 1H), 7.35 – 7.31 (m, 5H),
6.14 (d, J 2.0 Hz, 1H), 5.92 (dd, J 17.6, 10.8 Hz, 1H), 5.18 (dd, J 10.8, 1.2 Hz, 1H), 5.04 (dd, J 17.7, 1.2 Hz, 1H),
4.56 (d, J 12.0 Hz, 1H), 4.51 (d, J 12.0 Hz, 1H), 4.21 (d, J 1.9 Hz, 1H), 4.13 (dd, J 8.4, 2.7 Hz, 1H), 3.49 (dd, J 10.0,
2.6 Hz, 1H), 3.33 (dd, J 10.0, 8.4 Hz, 1H), 2.48 – 2.23 (m, 2H), 1.96 (d, J 1.2 Hz, 3H), 1.25 (t, J 7.4 Hz, 3H), 1.12 (s,
13
3H), 0.94 (s, 9H), 0.05 (s, 3H), 0.03 (s, 3H) ppm, OH signal missing possibly due to exchange in CDCl3; C NMR
(126 MHz, CDCl3) δ 163.6, 151.5, 140.5, 138.3, 138.1, 128.5, 127.9, 127.7, 117.0, 111.4, 79.3, 73.8, 73.4, 72.5,
64.4, 49.1, 26.5, 24.3, 19.1, 14.5, 14.4, 12.6, -1.4, -3.1 ppm; HRMS calcd for C28H44N2O5SSiNa [M+Na+]:
571.2632; found 571.2669 (+6.5 ppm).
(–)-1-{(1S,2R,3S)-3-[(S)-2-(Benzyloxy)-1-hydroxyethyl]-2-[(tert-butyldimethylsilyl)oxy]-1-(ethylthio)-3-
o
methylpent-4-en-1-yl}pyrimidine-2,4(1H,3H)-dione (31): To a 0 C solution of dithioacetal 4 (72 mg, 0.12
mmol, 1.0 equiv.) in THF (0.50 mL, 0.24 M), silylated uracil (0.90 M in DCE, 0.25 mL, 0.24 mmol, 2.0 equiv.) and
iodine (61 mg, 0.24 mmol, 2.0 equiv.) were added. The resulting dark purple reaction mixture was stirred 16
hours at 0 oC before addition of saturated aqueous Na2S2O3 (2 mL) followed by addition of a few drops of 2N
NaOH. The biphasic mixture was warmed to room temperature and stirred vigorously until a clear
homogeneous biphasic mixture was obtained. The aqueous layer was extracted with Et2O (2 × 2 mL) and the
combined organic fractions were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to
1
afford the crude thioaminal which was used directly in the next step. H NMR spectroscopic analysis of the
unpurified product indicated the formation of only one diastereomer. To a solution of the crude thioaminal in
CH2Cl2/MeOH (1:1, 6.0 mL, 0.020 M), TsOH·H2O (114 mg, 0.60 mmol, 5.0 equiv.) was added. The resulting
mixture was warmed to 50 oC and stirred for 16 hours. The reaction mixture was cooled to room temperature
and Et3N (0.10 mL, 0.72 mmol, 6.0 equiv.) was added. After evaporation of the volatiles, the residue was
purified by flash chromatography to afford 31 as a white foam (51 mg, 79% yield over two steps): Rf = 0.24
[]2D5
(Hexanes/EtOAc, 60:40);
-48 (c= 1.1, CH2Cl2); Molecular formula: C27H42N2O5SSi; MW: 534.79; IR (neat)
νmax 3427, 1684 cm-1; H NMR (500 MHz, CDCl3) δ 8.87 (s, 1H), 7.97 (d, J 8.2 Hz, 1H), 7.35 – 7.27 (m, 5H), 6.13
(d, J 1.6 Hz, 1H), 5.93 (dd, J 17.6, 10.9 Hz, 1H), 5.79 (appdd, J 8.1, 2.2 Hz, 1H), 5.19 (d, J 10.9 Hz, 1H), 5.05 (d, J
17.7 Hz, 1H), 4.56 (d, J 11.9 Hz, 1H), 4.50 (d, J 11.9 Hz, 1H), 4.21 (d, J 1.9 Hz, 1H), 4.13 – 4.09 (m, 1H), 3.50 (dd, J
9.9, 2.5 Hz, 1H), 3.38 (s, 1H), 3.33 (dd, J 9.8, 8.6 Hz, 1H), 2.44 – 2.29 (m, 2H), 1.24 (t, J 7.4 Hz, 3H), 1.12 (s, 3H),
1
13
0.92 (s, 9H), 0.04 (s, 3H), 0.02 (s, 3H) ppm; C NMR (126 MHz, CDCl3) δ 162.9, 151.4, 142.5, 140.4, 138.2,
128.5, 127.9, 127.8, 117.0, 102.8, 79.1, 73.6, 73.4, 72.3, 65.0, 49.1, 26.5, 24.4, 19.1, 14.42, 14.39, -1.5, -3.0
ppm; HRMS calcd for: C27H42N2O5SSiNa [M+Na+]: 557.2476; found 557.2470 (-1.1 ppm).
(–)-1-{(2R,3R,4S,5S)-5-[(Benzyloxy)methyl]-3-[(tert-butyldimethylsilyl)oxy)]-methyl-4-vinyltetrahydrofuran-
2-yl}-5-methylpyrimidine-2,4(1H,3H)-dione (32): To a stirred solution of 30 (0.21 g, 0.38 mmol, 1.0 equiv.) in
Page 24
©ARKAT USA, Inc

Arkivoc 2019, iv, 0-0
Lussier. T. et al.
THF (3.8 mL, 0.10 M), Me2S(SMe)BF4 (90 mg, 0.46 mmol, 1.2 equiv.) was added and the resulting mixture was
stirred 2 hours at room temperature. The reaction mixture was then diluted with Et2O (15 mL) followed by
addition of saturated aqueous NaHCO3. The aqueous phase was extracted with Et2O (1 × 15 mL) and the
combined organic fractions were washed with brine, dried over MgSO4, filtered and concentrated in vacuo.
Purification by flash chromatography on silica gel provided 32 as a white foam (0.42 g, 71% yield): Rf = 0.49
[]2D5
(Hexanes/EtOAc, 60:40);
-12 (c= 0.23, CH2Cl2); Molecular formula: C26H38N2O5Si; MW: 486.68; IR (neat)
νmax 3182, 3062, 2928, 1691, 1264 cm-1; H NMR (500 MHz, CDCl3) 7.92 (s, 1H), 7.76 (d, J 1.1 Hz, 1H), 7.39 –
7.30 (m, 5H), 6.14 (dd, J 17.5, 10.9 Hz, 1H), 6.09 (d, J 7.4 Hz, 1H), 5.29 (d, J 10.9 Hz, 1H), 5.25 (d, J 17.5 Hz, 1H),
4.64 (d, J 11.3 Hz, 1H), 4.54 (d, J 11.3 Hz, 1H), 4.37 (d, J 7.4 Hz, 1H), 3.89 (t, J 2.0 Hz, 1H), 3.77 (dd, J 10.7, 2.6
Hz, 1H), 3.55 (dd, J 10.7, 1.5 Hz, 1H), 1.38 (d, J 0.9 Hz, 3H), 1.33 (s, 3H), 0.81 (s, 9H), -0.04 (s, 3H), -0.16 (s, 3H)
ppm; C NMR (126 MHz, CDCl3) δ 163.4, 150.8, 139.8, 137.4, 136.6, 128.9, 128.4, 127.6, 117.5, 111.4, 87.2,
86.7, 79.8, 73.6, 71.4, 49.6, 25.7, 18.0, 17.8, 11.7, -4.1, -4.8 ppm; HRMS calcd for: C26H38N2O5SiNa [M+Na+]:
509.2442; found 509.2447 (+0.9 ppm).
1
13
(–)-1-{(2R,3R,4S,5S)-5-[(Benzyloxy)methyl]-3-[(tert-butyldimethylsilyl)oxy]-4-methyl-4-vinyltetrahydrofuran-
2-yl}pyrimidine-2,4(1H,3H)-dione (33): To a stirred solution of 31 (0.12 g, 0.22 mmol, 1.0 equiv.) in THF (2.2
mL, 0.10 M), Me2S(SMe)BF4 (55 mg, 0.28 mmol, 1.3 equiv.) was added and the resulting mixture was stirred 2
hours at room temperature. The reaction mixture was diluted with Et2O (5 mL) followed by addition of
saturated aqueous NaHCO3. The aqueous phase was extracted with Et2O (1 × 15 mL) and the combined
organic fractions were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification
by flash chromatography on silica gel provided 33 as a white foam (81 mg, 80% yield): Rf = 0.49
[]25
(Hexanes/EtOAc, 60:40);
-1.6 (c = 0.19, CH2Cl2); Molecular formula: C25H36N2O5Si; MW: 472.66; IR (neat)
D
νmax 3183, 3064, 2928, 1686, 1265, 1059, 837 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.93 (d, J = 8.2 Hz, 1H), 7.88 (s,
1H), 7.44 – 7.34 (m, 5H), 6.08 (dd, J = 17.5, 10.8 Hz, 1H), 6.06 (d, J = 7.3 Hz, 1H), 5.30 (dd, J = 10.9, 0.7 Hz, 1H),
5.24 (dd, J = 17.7, 0.8 Hz, 1H), 5.21 (dd, J = 8.2, 2.5 Hz, 1H), 4.61 (d, J = 10.4 Hz, 1H), 4.43 (d, J = 10.5 Hz, 1H),
4.26 (d, J = 7.3 Hz, 1H), 3.88 (dd, J = 2.2, 1.7 Hz, 1H), 3.75 (dd, J = 10.6, 2.6 Hz, 1H), 3.57 (dd, J = 10.6, 1.4 Hz,
1H), 1.31 (s, 3H), 0.79 (s, 9H), -0.10 (s, 3H), -0.22 (s, 3H) ppm; 13C NMR (126 MHz, CDCl3) δ 162.7, 150.7, 141.2,
139.7, 137.2, 129.0, 128.7, 128.3, 117.6, 102.5, 87.4, 86.9, 79.9, 73.9, 71.3, 49.7, 25.7, 17.9, 17.7, -4.2, -4.9
ppm; HRMS calcd for: C25H36N2O5SiNa [M+Na+]: 495.2286; found 495.2291 (+1.0 ppm).
Compounds 34, 35, 36 and 37 from Scheme 8:
(+)-1-{(2R,3R,4R,5S)-5-[(Benzyloxy)methyl]-3-hydroxy-4-(hydroxymethyl)-4-methyltetrahydrofuran-2-yl}-5-
methylpyrimidine-2,4(1H,3H)-dione (34): To a solution of alkene 32 (0.11 g, 0.22 mmol, 1.0 equiv.) in
acetone/H2O (2:1, 2.2 mL, 0.10 M), NMO (0.10 g, 0.86 mmol, 4.0 equiv.) and OsO4 (4% in H2O, 70 µL, 0.050
equiv.) were added. The resulting mixture was warmed to 50 oC and stirring was continued for 16 hours. After
cooling to room temperature, the reaction mixture was diluted with EtOAc (3 mL) and water (2 mL). The
aqueous layer was extracted with EtOAc (2x3 mL) and the combined organic fractions were washed with brine,
dried over MgSO4, filtered and concentrated in vacuo to provide the crude diol as a single diastereoisomer
(unassigned stereochemistry) which was used directly in the next step. The crude diol (0.22 mmol, 1.0 equiv.)
was dissolved in dioxane/H2O (9:1, 2.2 mL, 0.10 M) and the resulting solution was cooled to 0 oC followed by
addition of NaIO4 (94 mg, 0.44 mmol, 2.0 equiv.). The mixture was warmed to room temperature and stirring
was continued for 3 hours. The reaction mixture was diluted with EtOAc (2 mL) and slowly poured into stirring
cold saturated aqueous Na2S2O3. After stirring 15 minutes, the aqueous phase was extracted with EtOAc (2x3
mL) and the combined organic fractions were washed with brine, dried over MgSO4, filtered and concentrated
in vacuo to provide the crude aldehyde as a white solid. The crude aldehyde (0.22 mmol, 1.0 equiv.) was
dissolved in THF (2.2 mL, 0.10 M) and the resulting solution cooled to –40 oC. LiBH4 (2.0 M in THF, 0.14 mL,
Page 25
©ARKAT USA, Inc

Arkivoc 2019, iv, 0-0
Lussier. T. et al.
0.29 mmol, 1.3 equiv.) was added dropwise and stirring was continued for 2 hours. The reaction was
quenched with slow addition of 0.05N HCl (2 mL) and warmed to room temperature. After stirring vigorously
for 30 minutes, EtOAc (3 mL) was added and the aqueous phase extracted with EtOAc (2 × 3 mL). The
combined organic fractions were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to
provide the crude alcohol. The crude alcohol (0.22 mmol, 1.0 equiv.) was dissolved in THF (1.1 mL, 0.20 M) and
the resulting solution was cooled to 0 oC. TBAF (1.0 M in THF, 0.33 mL, 0.33 mmol, 1.5 equiv.) was added and
stirring at 0 oC was continued for 16 hours. The reaction mixture was diluted with EtOAc (3 mL) followed by
addition of saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc (2x3 mL) and the combined
organic fractions were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to provide the
crude diol. Purification by flash chromatography on silica gel provided the pure C5’-protected nucleoside 34 as
[]25
a white foam (49 mg, 59% yield over 4 steps): Rf = 0.64 (CH2Cl2/MeOH, 90:10); D +1.9 (c= 0.66, CH2Cl2/MeOH
1
10:1); Molecular formula: C19H24N2O6; MW: 376.41; IR (neat) νmax 3412, 1685 cm-1; H NMR (500 MHz, CDCl3)
δ 10.97 (s, 1H), 7.60 (s, 1H), 7.38 – 7.28 (m, 5H), 5.76 (d, J 4.4 Hz, 1H), 5.01 (s, 1H), 4.62 (d, J 11.6 Hz, 1H), 4.58
(d, J 11.6 Hz, 1H), 4.42 (s, 1H), 4.10 (t, J 3.6 Hz, 1H), 3.82 (dd, J 10.9, 3.4 Hz, 1H), 3.77 (dd, J 10.9, 3.9 Hz, 1H),
3.63 (s, 2H), 3.57 (s, 1H), 1.52 (s, 3H), 1.19 (s, 3H) ppm; 13C NMR (126 MHz, CDCl3) δ 164.5, 152.3, 137.4, 136.9,
128.8, 128.2, 127.9, 109.8, 91.8, 86.1, 78.4, 73.9, 69.2, 66.1, 48.0, 16.6, 12.3 ppm; HRMS calcd for
C19H24N2O6Na [M+Na+]: 399.1527; found 399.1527 (0.0 ppm).
(+)-1-{(2R,3R,4R,5S)-5-[(Benzyloxy)methyl]-3-hydroxy-4-(hydroxymethyl)-4-methyltetrahydrofuran-2-yl}-
pyrimidine-2,4(1H,3H)-dione (35): To a solution of alkene 33 (47 mg, 0.10 mmol, 1.0 equiv.) in acetone/H2O
(2:1, 1.0 mL, 0.10 M), NMO (47 mg, 0.40 mmol, 4.0 equiv.) and OsO4 (4% in H2O, 33 µL, 0.050 equiv.) were
added. The resulting mixture was warmed to 50 oC and stirring was continued for 16 hours. After cooling to
room temperature, the reaction mixture was diluted with EtOAc (2 mL) and water (1 mL). The aqueous layer
was extracted with EtOAc (2 × 2 mL) and the combined organic fractions were washed with brine, dried over
MgSO4, filtered and concentrated in vacuo to provide the crude diol as a single diastereoisomer (unassigned
stereochemistry) which was used directly in the next step. The crude diol was dissolved in dioxane/H2O (9:1,
1.0 mL, 0.10 M) and the resulting solution cooled to 0 oC followed by addition of NaIO4 (43 mg, 0.20 mmol, 2.0
equiv.). The mixture was warmed to room temperature and stirring was continued for 3 hours. The reaction
mixture was diluted with EtOAc (2 mL) and slowly poured into stirring cold saturated aqueous Na2S2O3. After
stirring 15 minutes, the aqueous phase was extracted with EtOAc (2 × 3 mL). The combined organic fractions
were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to provide the crude aldehyde
as a white solid. The crude aldehyde was dissolved in THF (1.0 mL, 0.10 M) and the resulting solution cooled to
-40 oC. LiBH4 (2.0 M in THF, 50 µL, 0.10 mmol, 1.0 equiv.) was added dropwise and stirring was continued for 2
hours. The reaction was quenched with slow addition of 0.05N HCl (2.5 mL) and warmed to room
temperature. After stirring vigorously for 30 minutes, EtOAc (3 mL) was added, and the aqueous phase was
extracted with EtOAc (2 × 3 mL). The combined organic fractions were washed with brine, dried over MgSO4,
filtered and concentrated in vacuo to provide the crude alcohol. The crude alcohol was dissolved in THF (0.50
mL, 0.20 M) and the resulting solution cooled to 0 oC. TBAF (1.0 M in THF, 0.15 mL, 0.15 mmol, 1.5 equiv.) was
added and stirring at 0 oC continued for 16 hours. The reaction mixture was diluted with EtOAc (3 mL) followed
by addition of saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc (2 × 3 mL) and the
combined organic fractions were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to
provide the crude diol. Purification by flash chromatography on silica gel provided the pure C5’ protected
[]25
nucleoside 35 as a white foam (21.7 mg, 59% yield over 4 steps): Rf = 0.61 (CH2Cl2/MeOH, 90:10);
+5.0 (c=
D
0.64, CH2Cl2/MeOH 10:1); Molecular formula: C18H22N2O6; MW: 362.38; IR (neat) νmax 3392, 1680 cm-1; 1H NMR
(500 MHz, CD3OD) δ 7.99 (d, J 8.1 Hz, 1H), 7.42 – 7.30 (m, 5H), 5.93 (d, J 6.9 Hz, 1H), 5.31 (d, J 8.1 Hz, 1H), 4.62
Page 26
©ARKAT USA, Inc

Arkivoc 2019, iv, 0-0
Lussier. T. et al.
(d, J 10.8 Hz, 1H), 4.49 (d, J 10.8 Hz, 1H), 4.08 (d, J 6.9 Hz, 1H), 3.99 (t, J 2.9 Hz, 1H), 3.89 – 3.79 (m, 3H), 3.59
13
(d, J 10.9 Hz, 1H), 1.24 (s, 3H) ppm, OH and NH signals missing possibly due to exchange in CD3OD; C NMR
(126 MHz, CD3OD) δ 166.1, 152.9, 142.9, 139.1, 129.7, 129.4, 129.2, 102.6, 89.6, 87.4, 77.8, 74.7, 71.5, 66.1,
49.0, 17.5 ppm; HRMS calcd for C18H22N2O6Na [M+Na+]: 385.1370; found 385.1369 (-0.3 ppm).
(+)-1-[(2R,3R,4R,5S)-3-Hydroxy-4,5-bis(hydroxymethyl)-4-(methyltetrahydrofuran-2-yl)]-5-methylpyrimidine-
2,4(1H,3H)-dione (36): To a –40 oC solution of benzyl ether 34 (47 mg, 0.13 mmol, 1.0 equiv.) in CH2Cl2 (3.1 mL,
0.025 M), BCl3 (1.0 M in CH2Cl2, 0.63 mL, 0.63 mmol, 5.0 equiv.) was added dropwise. The reaction mixture
was stirred for 3 hours, at which point, methanol (0.10 mL) was added. With warming to room temperature,
1
stirring was continued for 30 minutes and the volatiles removed under reduced pressure. H NMR analysis of
the crude reaction mixture showed an 8:1 mixture of the product and starting material. Purification by flash
chromatography (Biotage, C18 reverse phase, Water/MeOH) provided nucleoside 36 as a white foam (16.4
[]2D5
mg, 46% yield):
+3.2 (c= 1.3, MeOH); Molecular formula: C12H18N2O6; MW: 286.28; IR (neat) νmax 2322,
1667 cm-1; 1H NMR (500 MHz, CD3OD) δ 7.99 (d, J 1.1 Hz, 1H), 5.90 (d, J 6.9 Hz, 1H), 4.23 (d, J 6.8 Hz, 1H), 3.88
– 3.78 (m, 3H), 3.71 (d, J 11.2 Hz, 1H), 3.57 (d, J 11.2 Hz, 1H), 1.89 (d, J 0.9 Hz, 3H), 1.15 (s, 3H) ppm, OH and
NH signals missing possibly due to exchange in CD3OD; C NMR (126 MHz, CD3OD) δ 166.4, 153.1, 138.7,
111.6, 89.6, 88.5, 77.0, 65.5, 62.7, 48.6, 17.8, 12.5 ppm; HRMS calcd for C12H18N2O6Na [M+Na+]: 309.1057;
found 309.1065 (+2.6 ppm). See supporting information for proof of structure.
13
(+)-1-[(2R,3R,4R,5S)-3-Hydroxy-4,5-bis(hydroxymethyl)-4-methyltetrahydrofuran-2-yl]pyrimidine-2,4(1H,3H)-
dione (37): To a –40 oC solution of benzyl ether 35 (27 mg, 75 µmol, 1.0 equiv.) in CH2Cl2 (32 mL, 0.025 M), BCl3
(1.0 M in CH2Cl2, 0.37 mL, 0.37 mmol, 5.0 equiv.) was added dropwise. The stirred reaction mixture was slowly
warmed to –20 oC over 2 hours and stirred for 1 more hour at –20 oC, at which point methanol (0.10 mL) was
added. The cooling bath was removed and stirring continued for 30 minutes. The volatiles were removed
under reduced pressure. Purification by flash chromatography (Biotage, C18 reverse phase, Water/MeOH)
[]25
provided the nucleoside 37 as a white foam (16 mg, 79% yield):
+20 (c= 0.4, MeOH); Molecular formula:
D
C11H16N2O6; MW: 272.26; IR (neat) νmax 3369, 1681 cm-1; H NMR (500 MHz, CD3OD) δ 8.12 (d, J 8.1 Hz, 1H),
5.90 (d, J 6.6 Hz, 1H), 5.71 (d, J 8.0 Hz, 1H), 4.21 (d, J 6.6 Hz, 1H), 3.88 – 3.85 (m, 1H), 3.85 – 3.76 (m, 2H), 3.68
(d, J 11.1 Hz, 1H), 3.55 (d, J 11.1 Hz, 1H), 1.16 (s, 3H) ppm, OH and NH signals missing possibly due to exchange
in CD3OD; C NMR (126 MHz, CD3OD) δ 166.7, 153.3, 142.9, 102.9, 90.1, 88.7, 77.4, 65.4, 62.7, 48.7, 17.7
ppm; HRMS calcd for C11H16N2O6Na [M+Na+]: 295.0901; found 295.0902 (+0.3 ppm).
1
13
Acknowledgements
Funding for this research has been granted from Natural Sciences and Engineering Research Council (NSERC)
and Canadian Glycomics Network (Glyconet http://10.13039/501100009056). This research was enabled in
part by WestGrid (www.westgrid. ca) and Compute Canada−Calcul Canada (www. computecanada.ca).
Supplementary Material
The supporting information is available free of charge on the website and contains proof of structures, X-ray
1
13
crystallographic data for compound S20a, H NMR and C NMR spectra for all new compounds along with
details concerning the computational method, energies, and Cartesian coordinates for intermediate E.
Page 27
©ARKAT USA, Inc

Arkivoc 2019, iv, 0-0
Lussier. T. et al.
References
1. Jordheim, L. P.; Durantel, D.; Zoulim, F.; Dumontet, C. Nat. Rev. Drug Discovery 2013, 12, 447-464.
http://dx.doi.org/10.1038/nrd4010.
2. Seley-Radtke, K. L.; Yates, M. K. Antiviral Res. 2018, 154, 66-86.
http://dx.doi.org/10.1016/j.antiviral.2018.04.004.
3. Tsesmetzis, N.; Paulin, C. B. J.; Rudd, S. G.; Herold, N. Cancers 2018, 10, 240.
http://dx.doi.org/10.3390/cancers10070240.
4. Asselah, T. Expert Opin. Pharmacother. 2014, 15, 121-130.
http://dx.doi.org/10.1517/14656566.2014.857656.
5. Guindon, Y.; Mochirian, P.; Nemer, M.; Prévost, M. Nucleoside Analogues and Methods of use thereof,
2017, PCT/CA2017/051096.
6. Guindon, IRCM, Patent US8361988B2 (2013) and US8846636B2 (2014) US 62/218,220 (Sept 2015)
7. Tambutet, G.; Becerril-Jimenez, F.; Dostie, S.; Simard, R.; Prevost, M.; Mochirian, P.; Guindon, Y. Org. Lett.
2014, 16, 5698-5701.
http://dx.doi.org/10.1021/ol502777r.
8. Dostie, S.; Prevost, M.; Mochirian, P.; Tanveer, K.; Andrella, N.; Rostami, A.; Tambutet, G.; Guindon, Y. J.
Org. Chem. 2016, 81, 10769-10790.
http://dx.doi.org/10.1021/acs.joc.6b01845.
9. Panda, A.; Satpati, S.; Dixit, A.; Pal, S. RSC Adv., 2016, 6, 11233-11239.
http://dx.doi.org/10.1039/c5ra26416b.
10. Panda, A.; Islam, S.; Santra, M.; Pal, S. RSC Adv., 2015, 5, 82450-82459.
http://dx.doi.org/10.1039/c5ra19080k.
11. Sells, T.; Nair, V. Tet. Lett., 1993, 34, 3527-3530.
https://dx.doi.org/10.1016/S0040-4039(00)73627-6.
12. Zong, G.; Yan, X.; Bi, J.; Jiang, R.; Qin, Y.; Yuan, H.; Lu, H.; Dong, Y.; Jin, S.; Zhang, J. PLoS One 2017, 12,
e0181646.
http://dx.doi.org/10.1371/journal.pone.0181646.
13. Sun, J.; Dou, Y.; Ding, H.; Yang, R.; Sun, Q.; Xiao, Q. Mar Drugs 2012, 10, 881-889.
http://dx.doi.org/10.3390/md10040881.
14. Reddy, E. R.; Trivedi, R.; Sudheer Kumar, B.; Sirisha, K.; Sarma, A. V.; Sridhar, B.; Prakasham, R. S. Bioorg.
Med. Chem. Lett. 2016, 26, 3447-3452.
http://dx.doi.org/10.1016/j.bmcl.2016.06.049.
15. Gonçalves-Pereira, R.; Pereira, M.; Serra, S.; Loesche, A.; Csuk, R.; Silvestre, S.; Costa, P.; Conceição
Oliveira, M.; Xavier, N. Eur. J. Org. Chem. 2018, 2667-2681.
http://dx.doi.org/10.1002/ejoc.201800245.
16. Guindon, Y.; Houde, K.; Prevost, M.; Cardinal-David, B.; Landry, S. R.; Daoust, B.; Bencheqroun, M.; Guerin,
B. J. Am. Chem. Soc. 2001, 123, 8496-8501.
https://dx.doi.org/10.1021/ja010805m.
17. Brazeau, J. F.; Mochirian, P.; Prevost, M.; Guindon, Y. J. Org. Chem. 2009, 74, 64-74.
http://dx.doi.org/10.1021/jo8021583.
18. Kita, Y.; Yasuda, H.; Tamura, O.; Itoh, F.; Ya, Y. K.; Tamura, Y. Tetrahedron Lett. 1985, 26, 5777-5780.
https://dx.doi.org/10.1016/S0040-4039(00)98924-X.
19. Dong, S.; Parker, G. D.; Tei, T.; Paquette, L. A. Org. Lett. 2006, 8, 2429-2431.
Page 28
©ARKAT USA, Inc

Arkivoc 2019, iv, 0-0
Lussier. T. et al.
http://dx.doi.org/10.1021/ol060827j.
20. Paquette, L. A.; Parker, G. D.; Tei, T.; Dong, S. J. Org. Chem. 2007, 72, 7125-7134.
http://dx.doi.org/10.1021/jo070861r.
21. Paquette, L. A.; Parker, G. D.; Tei, T.; Dong, S. J. Org. Chem. 2009, 74, 1812.
http://dx.doi.org/10.1021/jo9001382.
22. Duplessis, M.; Waltz, M. E.; Bencheqroun, M.; Cardinal-David, B.; Guindon, Y. Org. Lett. 2009, 11, 3148-
3151.
http://dx.doi.org/10.1021/Ol901126y.
23. Giese, B.; Damm, W.; Wetterich, F.; Zeltz, H.G.; Rancourt, J.; Guindon, Y. Tetrahedron Lett. 1993, 34, 5885-
5888.
https://dx.doi.org/10.1016/S0040-4039(00)73805-6.
24. Ward, D. E.; Hrapchak, M. J.; Sales, M. Org. Lett. 2000, 2, 57-60.
http://dx.doi.org/10.1021/ol991198z.
25. North, M.; Usanov, D. L.; Young, C. Chem. Rev. 2008, 108, 5146-5226.
http://dx.doi.org/10.1021/cr800255k.
26. Denmark, S. E.; Chung, W. J. J. Org. Chem. 2006, 71, 4002-4005.
http://dx.doi.org/10.1021/jo060153q.
27. Shenoy, S. R.; Smith, D. M.; Woerpel, K. A. J. Am. Chem. Soc. 2006, 128, 8671-8677.
http://dx.doi.org/10.1021/ja061110u.
28. Kurono, N.; Yamaguchi, M.; Suzuki, K.; Ohkuma, T. J. Org. Chem. 2005, 70, 6530-6532.
http://dx.doi.org/10.1021/jo050791t.
29. Yajima, T.; Okada, K.; Nagano, H. Tetrahedron 2004, 60, 5683-5693.
http://dx.doi.org/10.1016/j.tet.2004.05.020.
30. Nagano, H.; Ohkouchi, H.; Yajima, T. Tetrahedron 2003, 59, 3649-3663.
http://dx.doi.org/10.1016/S0040-4020(03)00421-6.
31. Nagano, H.; Toi, S.; Matsuda, M.; Hirasawa, T.; Hirasawa, S.; Yajima, T. J. Chem. Soc. Perkin Trans. I 2002,
2525-2538.
http://dx.doi.org/10.1039/b205613p.
32. However, PMBCl or PMBOH could not be observed in the NMR spectra.
33. Gau, H.-M.; Lee, C.-S.; Lin, C.-C.; Jiang, M.-K.; Ho, Y.-C.; Kuo, C.N. J. Am. Chem. Soc. 1996, 118, 2936-2941.
http://dx.doi.org/10.1021/ja952730q.
34. Gaussian 09, Revision D.01, M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R.
Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P.
Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J.
Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery, Jr., J. E.
Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, T. Keith, R. Kobayashi,
J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M.
Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O.
Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzewski, G.
A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, O. Farkas, J. B. Foresman, J. V. Ortiz, J.
Cioslowski, and D. J. Fox, Gaussian, Inc., Wallingford CT, 2013.
35. Zhao, Y.; Truhlar, D. G. Acc. Chem. Res. 2008, 41, 157-167.
http://dx.doi.org/10.1021/ar700111a.
36. Cossi, M.; Scalmani, G.; Rega, N.; Barone, V. J. Chem. Phys. 2002, 117, 43-54.
Page 29
©ARKAT USA, Inc

Arkivoc 2019, iv, 0-0
Lussier. T. et al.
http://dx.doi.org/10.1063/1.1480445.
37. Godin, F.; Duplessis, M.; Buonomano, C.; Trinh, T.; Houde, K.; Chapdelaine, D.; Rodrigue, J.; Boutrosa, A.;
Guindon, Y. Org. Chem. Front., 2014, 1, 974-982.
http://dx.doi.org/10.1039/c4qo00142g.
38. Kang, M.; Park, J.; Pedersen, S. F. Synlett 1997, 41-43.
http://dx.doi.org/10.1055/s-1997-709.
39. Park, J.; Pedersen, S. F. J. Org. Chem. 1990, 55, 5924-5926.
http://dx.doi.org/10.1021/jo00311a002.
40. Chapdelaine, D.; Cardinal-David, B.; Prevost, M.; Gagnon, M.; Thumin, I.; Guindon, Y. J. Am. Chem. Soc.
2009, 131, 17242-17245.
http://dx.doi.org/10.1021/ja905452f.
41. Prevost, M.; Dostie, S.; Waltz, M. E.; Guindon, Y. J. Org. Chem. 2014, 79, 10504-10525.
http://dx.doi.org/10.1021/jo502181a.
42. Solsona, J.; Romea, P.; Urpi, F.; Vilarrasa, J. Org. Lett. 2002, 4, 519-522.
http://dx.doi.org/10.1021/ol0274054.
43. De Esch, I. J.; Gaffar, A.; Menge, W. M.; Timmerman, H. Bioorg. Med. Chem. 1999, 7, 3003-3009.
https://dx.doi.org/10.1016/S0968-0896(99)00253-9.
44. Maulucci, N.; Izzo, I.; Bifulco, G.; Aliberti, A.; De Cola, C.; Comegna, D.; Gaeta, C.; Napolitano, A.; Pizza, C.;
Tedesco, C.; Flot, D.; De Riccardis, F. Chem. Commun. (Camb) 2008, 3927-3929.
http://dx.doi.org/10.1039/b806508j.
45. Iseki, K.; Kuroki, Y.; Asada, D.; Takahashi, M.; Kishimoto, S.; Kobayashi, Y. Tetrahedron 1997, 53, 10271-
10280.
https://dx.doi.org/10.1016/S0040-4020(97)00683-2.
Page 30
©ARKAT USA, Inc