Unified Strategy for 1,5,9- and 1,5,7-Triols via Configuration-Encoded 1,5-Polyol Synthesis: Enantioselective Preparation of γ-Sulfonyl-α-silyloxyaldehydes and Iterative Julia-Kocienski Coupling

Article abstract of DOI:10.1021/acs.joc.8b02033

Diverse classes of natural products contain chiral 1,5-polyols, within which may be stereochemical triads of 1,5,9- and 1,5,7-triols. Biological activities associated with compounds containing these motifs warrant targeted synthetic strategies to access all stereoisomers of a 1,5-polyol family from cheap and easily accessible reagents while avoiding the need to determine configurations at each alcohol stereocenter. Here, we address these problems via design and implementation of an iterative configuration-encoded strategy to access 1,5-polyols with unambiguous stereocontrol; the coupling event exploits Julia-Kocienski reactions of enantiopure α-silyloxy-γ-sulfononitriles. These building blocks, bearing sulfone at one terminus and α-silyloxyaldehyde (in latent form) at the other, were prepared via asymmetric catalysis. An efficient scalable route to these building blocks was developed, leading to enantiopure samples in multigram quantities. Preliminary studies of acetals as the latent aldehyde functionality in the α-silyloxyaldehyde showed that Julia-Kocienski coupling of these building blocks was effective, but iterative application was thwarted during acetal hydrolysis, leading to use of nitrile to perform the latent aldehyde function. A variety of 1,5-polyols, including a 1,5,9,13-tetraol and a differentially protected 1,5,9-triol, were prepared, validating the approach. The accompanying paper describes the application of this configuration-encoded 1,5-polyol synthesis to 1,5,9- and 1,5,7-triols found in tetrafibricin.

Full text of DOI:10.1021/acs.joc.8b02033

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Featured Article
Unified Strategy for 1,5,9- and 1,5,7-Triols via Configuration-
Encoded 1,5-Polyol Synthesis: Enantioselective Preparation of #-
Sulfonyl-#-silyloxyaldehydes and Iterative Julia–Kocienski Coupling
Ryan M. Friedrich, Gopeekrishnan Sreenilayam, Jacob Hackbarth, and Gregory K Friestad
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02033 • Publication Date (Web): 26 Oct 2018
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Unified Strategy for 1,5,9- and 1,5,7-Triols via Configuration-Encoded
1,5-Polyol Synthesis: Enantioselective Preparation of -Sulfonyl-
-silyloxyaldehydes and Iterative Julia–Kocienski Coupling
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‡
†
Ryan M. Friedrich , Gopeekrishnan Sreenilayam , Jacob Hackbarth, and Gregory K.
Friestad*
Department of Chemistry, University of Iowa, Iowa City, Iowa 52242 USA
email: gregory-friestad@uiowa.edu
Abstract: Diverse classes of natural products contain chiral 1,5-polyols, within which may
be stereochemical triads of 1,5,9- and 1,5,7-triols. Biological activities associated with
compounds containing these motifs warrant targeted synthetic strategies to access all
stereoisomers of a 1,5-polyol family from cheap and easily accessible reagents while avoiding
the need to determine configurations at each alcohol stereocenter. Here we address these
problems via design and implementation of an iterative configuration-encoded strategy to
access 1,5-polyols with unambiguous stereocontrol; the coupling event exploits Julia–Kocienski
reactions of enantiopure α-silyloxy-γ-sulfononitriles. These building blocks, bearing sulfone at
one terminus and α-silyloxyaldehyde (in latent form) at the other, were prepared via
‡
†
Current Address: Department of Genetics and Genome Sciences, Small-Molecule Drug Development Core, Case Western Reserve University
Current Address: Department of Chemistry, Valdosta State University
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asymmetric catalysis. An efficient scalable route to these building blocks was developed, leading
to enantiopure samples in multigram quantities. Preliminary studies of acetals as the latent
aldehyde functionality in the α-silyloxyaldehyde showed that Julia–Kocienski coupling of these
building blocks was effective, but iterative application was thwarted during acetal hydrolysis,
leading to use of nitrile to perform the latent aldehyde function. A variety of 1,5-polyols,
including a 1,5,9,13-tetraol and a differentially protected 1,5,9-triol were prepared, validating
the approach. The accompanying paper describes the application of this configuration-encoded
1,5-polyol synthesis to 1,5,9- and 1,5,7-triols found in tetrafibricin.
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1. Introduction
Naturally occuring compounds bearing 1,5-polyol structures present bioactivities of
potential utility in drug discovery; representative examples (Figure 1) include tetrafibricin1
(antithrombotic) and muricapentocin2 (anticancer). Further illustrating the breadth in
association of biological activities with 1,5-polyols are lydicamycin3 (antibiotic active against
multidrug resistant strains), sporminarin B4 (antifungal), and amphidinol 35 (hemolytic and
antifungal). Despite their common occurence in biologically active compounds, there are only a
handful of published methodologies addressing the synthesis and stereochemical assignment
of chiral 1,5-polyols.6 Strategies for the construction and characterization of 1,3-polyols have
been well documented,7 however, few are easily adaptable to 1,5-polyols. Applying biomimetic
polyketide and other aldol-based methodologies used for the synthesis of 1,3-polyols would
require selective dehydration after assembly, a prospect fraught with challenges of
regioselectivity and stereoselectivity. Additionally, the isolated hydroxyl stereocenters of 1,5-
diols make relative and absolute configuration assignments nontrivial.8 As with muricapentocin
(Figure 1), this analytical obstacle results in natural products isolation disclosures lacking
complete stereostructures; it also impedes any synthetic chemist seeking secure configurational
assignments en route to natural products of this class.
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The variety of structures found in 1,5-polyols includes syn- and anti-diastereromerism,
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saturation or unsaturation, and E/Z olefin isomers. Selected hydroxyl groups may be engaged
in macrolactone ester linkages. Notably, a 1,5-diol may be flanked by 1,3-diols in a 1,5,7-triol
stereotriad. Thus, we sought a unified approach to preparing all stereoisomeric 1,5-polyols, as
well as the variants just mentioned. A guiding inspiration was provided by tetrafibricin, which
contains both 1,5,9-triol and 1,5,7-triol motifs (Figure 1).
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In the last few years, several strategies have emerged to specifically target the chiral 1,5-diols
present in tetrafibricin and related targets.9,10,11,12,13,14,15,16,17,18,19 Some limitations and
disadvantages inherent to the prior art include the use of cumbersome reaction conditions (e.g.
toxic metals or high pressures), expensive chiral reagents used in stoichiometric quantities, and
different reagents required for different stereoisomers. In many cases, assigning the new
configuration of each remotely generated alcohol stereogenic center also adds extra steps to the
workflow.
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Figure 1
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Figure 1. Occurrence and importance of 1,5-polyol structures. (a) Bioactive natural
products presenting the 1,5-polyol motif. (b) Targeted substructures for
new strategic innovation.
To evade the aforementioned disadvantages, we envisioned an iterative strategy to access
1,5-polyols with unambiguous stereocontrol by encoding the configuration of each alcohol
stereogenic center within repeating enantiopure building blocks prepared via asymmetric
catalysis. Then, sequential coupling of these building blocks, choosing the correct configuration
at each stage, would allow for preparation of any diastereomeric 1,5-polyol with equal facility,
using the same coupling chemistry. For the coupling reactions, we chose the reliable Julia–
Kocienski method,20,21 using reagents readily available to most practitioners. Each building
block would need sulfone and aldehyde termini, as depicted in α-siloxy-γ-sulfonyl aldehyde
building block 1 (Scheme 1), with the aldehyde in latent form. In an iterative sequence, the
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coupling would take place between the sulfone of 1 and the aldehyde of a growing 1,5-polyol
chain; the latent aldehyde carried by the building block would then be revealed for another
iteration of the Julia–Kocienski olefination. This is a strategy-level innovation that allows for the
efficient and rapid access to syn and anti stereoisomers of a 1,5-polyol family from readily
accessible materials, without the need to determine the configuration of each alcohol
stereocenter in the growing polyol chain.
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The development of the aforementioned strategy is presented in this full account,22 detailing
the design and enantioselective synthesis of a -hydroxysulfone building block and its
implementation in preparation of various 1,5-polyol structures; the accompanying paper23
describes application of this approach to a natural product of this class, tetrafibricin.
Scheme 1
OH
OH
OH
R
OHC
OP SO2Ar
OP SO2Ar
OP SO2Ar
R
O
O
O
O
(build from right to left)
START
[Si]O
SO2PT
(R)-1
[Si]O
OHC
SO2PT
(S)-1
(S)-2
OHC
(R)-2
OHC = latent aldehyde: nitrile (1) or acetal (2)
[Si] = TBS or TBDPS
2. Results and Discussion
Acetal Configuration-Encoded Building Block. In our initial attempt to implement the
design hypothesis outlined in Scheme 1, acetal functionality was envisioned as a latent form of
the aldehyde in configuration-encoded polyol building block because of (a) its orthogonality to
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the Julia–Kocienski coupling conditions, and (b) its expected ease of hydrolysis. To test this, we
then needed access to α-silyloxyaldehyde acetal with a structure exemplified by 2a (Figure 2).
Examples of classical methods to access enantiopure α-silyloxyaldehydes are often unwieldy
and limited, as we found in the course of other projects.24 These include a six step sequence from
malic acid to generate aldehyde 425 and an eleven step sequence from D-mannitol to generate
aldehyde 526 (Figure 2b). Although Jacobsen’s kinetic resolution27 and organocatalytic α-
oxidation of aldehydes28 have offered improved alternatives to access to terminal 1,2-
difunctional compounds, the selective manipulation of functionality in 1,2-diols can still be
laborious. Thus, we devised a more direct and efficient route to -silyloxyaldehydes and their
corresponding acetal derivatives (e.g., 2) via an oxidative sequence employing ring-opening of
enol ester epoxides induced by a silyl electrophile (A  B  C).29 Combining this proposed
sequence with known access to enol esters from alkynes would lead to a generally useful
protocol to prepare -silyloxyaldehydes from alkynes.
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Figure 2
Figure 2. -Silyloxyaldehyde synthesis. (a) Plan for silyl cation-induced ring-opening.
(b) Selected examples of literature preparations.
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The required preparation of -silyloxyaldehyde acetal 2a presented an opportunity to test
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the feasibility of the hypothesized silyl cation-mediated epoxide-opening cascade. Thus, Z-enol
ester 6 (Scheme 2) was generated using a homoenolate aldol reaction, homologating Hoppe's
allyl carbamate anion30 with formaldehyde in 74% yield. Mitsunobu reaction with N-
phenyltetrazolylthiol followed by ammonium molybdate-catalyzed oxidation of sulfide 7
provided the corresponding sulfone 8. The enol ester was next epoxidized with
dimethyldioxirane (DMDO) to furnish chromatographically stable epoxide 9 in quantitative
isolated yield. Upon treatment of 9 with TBSOTf and 2,6-lutidine at room temperature, aldehyde
10 was obtained in 80% yield, showing that the ring-opening pathway was indeed feasible. For
characterization, the aldehyde was smoothly converted to the corresponding dimethyl acetal 2
in 86% yield under routine conditions (HC(OMe)3, TsOH, MeOH). Subsequently, a brief scope
study reported elsewhere31 revealed that linking this enol ester epoxide opening cascade with
the Goossen synthesis of enol esters from alkynes32 produced a rapid three-step sequence to
prepare -silyloxyaldehydes from alkynes.
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Scheme 2
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Although enantiomerically enriched -silyloxyaldehyde 10 could potentially be accessed by
employing an asymmetric epoxidation33 of ene-carbamate 8 prior to the epoxide opening, we
also explored an alternative access via catalytic asymmetric cyanohydrin construction.34 Most
methods for this are not well-adapted to aliphatic aldehyde precursors,35 but commercially
available chiral C2-symmeric Al(salen) catalyst 11 showed promise in such cases.36 This
approach began by engaging acrolein (12) in a conjugate addition reaction with 1-
phenyltetrazolyl-5-thiol (PTSH, 13) in the presence of catalytic triethylamine; this provided the
3-thiopropanal derivative 14 in 95% yield on multi-gram scale. Asymmetric addition of TMSCN
in the presence of Al(salen) catalyst (S,S)-11 (1 mol%) and additive Ph3PO (10 mol%) at low
temperature furnished an O-TMS cyanohydrin that proved difficult to handle and store.
However, following the cyanation with an aqueous acidic workup afforded the free
cyanohydrin 15a in 85% yield. A more robust silyl protecting group (TBS) was then installed
under standard conditions to provide O-silyl cyanohydrin (R)-15b in 84% yield; at this stage
chiral HPLC indicated ee values in the range of 44–50% for this sequence.37 Oxidation with
peroxide under ammonium molybdate catalysis gave the corresponding sulfone (R)-1a. Then,
reduction of the nitrile (DIBAL-H) and treatment of the resulting -silyloxyaldehyde with
triethyl orthoformate and catalytic TsOH furnished acetal (R)-2b in moderate yield.
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Scheme 3
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With two acetal versions of the configuration-encoded building block in hand (2a and (R)-
2b), Julia–Kocienski couplings were next examined. Several preliminary experiments with 2a
indicated that sequential treatment with base and benzaldehyde, isobutyraldehyde, or (S)-2-tert-
butyldimethylsiloxypropanal led to successful olefination.38 In order to render this an iterative
process, acetal hydrolysis would next be needed, and unfortunately numerous efforts to achieve
this resulted in complex mixtures. Precedent suggested that the diethyl acetal might be more
easily hydrolyzed.39
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Equation 1
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Toward this objective, Julia–Kocienski coupling of (R)-2b with benzaldehyde (Equation 1)
furnished alkene 16 (E/Z > 98:2). Considerable effort was dedicated to screening various
conditions for acetal hydrolysis of 16. Under all conditions attempted, the material was either
returned unchanged or produced intractible mixtures and low mass balance.40 Eventually, we
concluded that the silyl protection was not sufficiently orthogonal to acetal hydrolysis in this
instance. Nevertheless, the promising Julia–Kocienski couplings were encouraging toward
further exploration of the configuration-encoded strategy for 1,5-polyol synthesis.
Nitrile Configuration-Encoded Building Block. Cyanohydrin (R)-1a, obtained along the
synthetic route to acetal 2b (Scheme 3), was not initially prioritized due to concerns about
racemization under Julia–Kocienski coupling conditions.41 However, the orthogonality problem
observed during attempted hydrolysis of 16 refocused our attention on (R)-1a because it would
allow unmasking of the latent -silyloxyaldehyde by hydride reduction instead of hydrolysis.
Fortunately the racemization concerns were eliminated by two key experiments that established
retention of the O-silylcyanohydrin configuration during sulfone metalation. First,
deprotonation of (R)-1a (44% ee) with NaHMDS and quenching with water (Equation 2)
returned (R)-1a (99% recovery) with complete retention of the enantiomeric excess, as judged by
HPLC. Secondly, enantiopure (R)-1a (prepared by a different method, vide infra) was exposed to
the same metalation conditions followed by Julia–Kocienski coupling with benzaldehyde
(Equation 3), and HPLC analysis of the isolated product 17 again indicated complete retention
(99% ee).
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Equations 2 and 3
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Improved enantioselectivity in the cyanation step was eventually achieved using a chiral Ti
catalyst generated from a bifunctional BINOL ligand introduced for cyanation by Gau and
You.42 Thus, reaction of aldehyde 14 with excess TMSCN and the catalyst generated in situ from
Ti(OiPr)4 and chiral ligand (R)-18 at –20 °C afforded cyanohydrin (S)-15a (Scheme 4). At 1 mol%
catalyst loading, the reaction proceeded in 67% yield and 33% ee (HPLC after conversion to the
O-TBS derivative (S)-15b). Screening catalyst loadings of 5, 8, and 10 mol% revealed that the
yields reached 85–90% at 5 mol%, but the selectivity was only 78% ee, even at 10 mol%. Lowering
the temperature to –50 °C improved both yield and selectivity, affording a 99% yield and 90%
ee.43
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Scheme 4
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The optimized sequence (Scheme 4) furnished similarly high yields and selectivities for both
enantiomeric sulfone building blocks (R)- and (S)-1a, and was easily scalable to approximately
10 grams. The chiral ligand 18 was isolated with a recovery of 70–90%, and was successfully re-
used in the sequence. Absolute configuration in the series leading to (R)-1a was assigned using
MPA ester analysis; desilylation of (R)-1a (TsOH in aq. MeOH) and separate EDCI-mediated
esterifications with (R)- and (S)-methoxyphenyl acetic acid smoothly furnished the MPA esters
for this purpose.44
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Although material of 90% ee may be suitable for many synthetic applications, we recognized
that the proportion of desired stereoisomer would diminish at each stage if this level of purity
were to be employed in an iterative sequence. In considering how to bolster enantiopurity, we
noted that a solid was formed after the final oxidation step to sulfone 1a (Scheme 4), so
recrystallization from ethyl acetate/petroleum ether was examined. Fortuitous observations
during early attempts revealed that careful physical separation of crystals of two different habits
(Figure 3) offered enantiomeric resolution.45 Crystals appearing as transparent prisms of
approximately 1-4 mm proved to be racemic, and those appearing as a white powder (very fine
colorless needles on closer inspection) were enantiomerically pure, as judged by HPLC.
Subsequently, we noticed that the racemic material could be selectively crystallized in the first
crystallization, and then the second and third crops furnished 1a with the ee enriched to >99%
(HPLC).
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enantiomerically pure
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racemic
1 cm
Figure 3. Two different crystal habits obtained upon recrystallization of
enantiomerically enriched 1a from EtOAc and petroleum ether. At top
left, very fine colorless needles of enantiomerically pure 1a. At bottom
right, larger prisms of racemic 1a.
Application to Iterative 1,5-Polyol Synthesis. Preliminary studies of the application of
nitrile configuration-encoded building block 1a confirmed the utility of both enantiomers in
Julia–Kocienski couplings with simple unfunctionalized aldehydes, affording alkenes 17 and 19
(Table 1).22 Screening of Julia–Kocienski conditions revealed very high yields and E-selectivities
were obtained using either NaHMDS or KHMDS in THF at low temperature. Coupling reactions
employing the sodium and potassium counterions were roughly similar in their E-selectivity,
but LiHMDS led to noticeably lower selectivity. Coupling of 1a with -silyloxyaldehydes
derived from lactic acid or leucine showed the feasibility of constructing diastereomeric 1,5-
diols exemplified by 20 and 21.
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Table 1. Julia–Kocienski Couplings of 1a.
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Next, iterative application of the configuration-encoded synthesis required exposing the
reactive aldehyde at the polyol terminus. Reaction of nitrile 17 to DIBAL-H led to the
corresponding aldehyde, used in turn as the precursor for separate coupling experiments with
R and S configurations of the -sulfononitrile building block 1a to afford diastereomerically pure
samples of (R,R)-22 and (S,R)-22. These two successive Julia–Kocienski couplings were carried
out with enantiomeric building blocks, furnishing both the syn and anti diastereomers of 22
under otherwise identical conditions, and highlighting the simplicity with which this strategy
controls relative stereochemistry. The iterative nature of the approach was demonstrated to
three successive couplings upon O-silyl-lactaldehyde 23, affording convenient access to 1,5,9,13
tetraol 25 in diastereomerically pure form (Scheme 5).
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Scheme 5
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Hydroxyl Differentiation. Selective manipulations of the hydroxyl groups of a 1,5-polyol
may be desired in certain synthetic contexts, such as ensuring the correct ring size in
macrolactonization. To address this, we sought to replace the tert-butyldimethylsilyl group in
building block (R)-1a with an alternative silyl group. We opted for the modulated reactivity
approach, allowing for selective removal of TBS from a 1,5-polyol in the presence of a tert-
butyldiphenylsilyl (TBDPS). The most direct route to this alternative building block (R)-1b
(Scheme 6) follows the same sequence as for the TBS-protected analog, beginning with the
asymmetric cyanation of aldehyde 14. Silylation of cyanohydrin (R)-15a with TBDPSCl and
imidazole, followed by oxidation with ammonium molybdate smoothly furnished (R)-1b.
Unfortunately this waxy solid was not amenable to enantioenrichment via recrystallization.
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Scheme 6
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We returned to further optimize the cyanation step, and eventually, we found that allowing
more time in between the slow addition of reagents and careful temperature control in cannula
transfer, we were able to increase the enantioselectivity in the cyanation step to 94% ee without
lower temperature and unacceptably long reaction time. Others have speculated that the
condition of the TMSCN reagent may lead to variable selectivity due to the variations in the
amount of HCN present.41a Although the cyanohydrin (R)-15a (75% yield) was smoothly
transformed to the sulfone building block (R)-1b of 94% ee, enantiopure material (99% ee or
higher) was desired. An alternate route achieved this. Removal of the TBS group from the TBS-
protected (R)-1a (>99% ee after recrystallization) with p-TsOH afforded cyanohydrin (R)-1c (99%
yield) with no erosion of enantiopurity (as judged by optical rotation after reinstallation of the
TBS group). Installation of the TBDPS group as before furnished enantiopure alternate α-siloxy-
γ-sulfononitrile building block (R)-1b in 98% yield (>99% ee as judged by HPLC).
Scheme 7
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With both TBS and TBDPS building blocks of high enantiopurity at hand, their application
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in iterative coupling was examined (Scheme 7). Julia–Kocienski coupling of glycolaldehyde
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7
derivative 2646 with building block (S)-1a (KHMDS in 1,2-dimethoxyethane) gave olefin 27a in
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86% yield and E/Z = 90:10 (by H NMR and confirmed by GC-HRMS). Hydride reduction
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(DIBAL-H, toluene) furnished aldehyde 27b (79% yield). In this case the workup required some
optimization to minimize racemization;47 the optimized protocol entailed washing the crude
with very dilute (0.1 mM) aqueous tartaric acid and promptly using the aldehyde in the next
step. Another iteration of the Julia–Kocienski coupling, this time with alternative sulfone
building block (R)-1b bearing a TBDPS-protected hydroxyl, furnished anti-1,5-diol 28 in 66%
yield with excellent selectivity (E,E/Z,E >95:5, 19S/19R 97:3). This sequence demonstrates that
the configuration-encoded 1,5-polyol synthesis can be accomplished with differential
protection, opening the option of selective functionalization at one specific hydroxyl among
many.
3. Conclusion
In conclusion, efficiency and selectivity advantages have been demonstrated in a
configuration-encoded iterative approach to 1,5-polyol synthesis. Enantioselective and scalable
preparation of -sulfonyl--silyloxylaldehyde building blocks, with the aldehyde functionality
in latent form, enables convenient and reliable coupling chemistry with reagents that are readily
available in most synthesis laboratories. Importantly, encoding the alcohol configurations
within the building block mitigates the analytical and separations challenges inherent to
alternative approaches that generate new stereogenic centers in the coupling events. Extension
to a differentially protected 1,5,9-triol and a 1,5,9,13-tetraol indicate there is considerable
potential for broader applications in synthesis of complex molecular targets in the 1,5-polyol
class.
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Experimental Section
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Materials and Methods. Reactions employed oven- or flame-dried glassware under nitrogen
unless otherwise noted. THF, diethyl ether, CH2Cl2, benzene and toluene were purchased
inhibitor-free, sparged with argon, and passed through columns of activated alumina prior to
use (dropwise addition of blue benzophenone ketyl solution revealed the THF purified in this
manner sustained the blue color more readily than the control sample purified by distillation).
Nitrogen was passed successively through columns of anhydrous CaSO4 and R3-11 catalyst for
removal of water and oxygen, respectively. All other materials were used as received from
commercial sources unless otherwise noted. Thin layer chromatography (TLC) employed glass
0.25 mm silica gel plates with UV indicator. Flash chromatography columns were packed with
230-400 mesh silica gel as a slurry in the initial elution solvent. Gradient flash chromatography
was conducted by adsorption of product mixtures on silica gel, packing over a short pad of clean
silica gel as a slurry in hexane, and eluting with a continuous gradient from hexane to the
indicated solvent. Radial chromatography refers to centrifugally accelerated thin-layer
chromatography performed with a Chromatotron using commercially supplied rotors. Melting
points are uncorrected. Nuclear magnetic resonance (NMR) data were obtained at operating
frequencies of 600, 500, 400, or 300 MHz for 1H and 150, 125, 100 or 75 MHz for 13C, respectively.
Infrared spectra were recorded using a single beam FT-IR spectrophotometer by standard
transmission methods or by use of an attenuated total reflectance (ATR) probe. Optical rotations
were determined using a digital polarimeter operating at ambient temperature. Low- and high-
resolution mass spectra were obtained using sample introduction by dip, liquid
chromatography or gas chromatography. Combustion analyses were obtained from external
commercial services. Chromatographic diastereomer ratio analyses employed GCMS with 15
mL x 0.25 mm I.D. x 0.25  F.T. 5%-phenyl-95%-dimethylsiloxane column and helium as mobile
phase or HPLC with Microsorb-MV Si 8um 100A or Chiralcel OD columns (2-propanol/hexane
as mobile phase) or Chirex 3014 column (chloroform/hexane as mobile phase).
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(Z)-4-Hydroxybut-1-enyl diisopropylcarbamate (6). To a solution of O-allyl N,N-
diisopropylcarbamate (150 mg, 0.81 mmol) and (–)-sparteine (0.23 mL, 0.97 mmol) in toluene
(7.5 mL) at –78 ºC was added n-BuLi (0.43 mL, 0.97 mmol) slowly over a period of 30 min. After
2 h at –78 ºC, a chilled (–78 ºC) solution of fresh titanium tetraisopropoxide (0.67 mL, 2.4 mmol)
in toluene (2 mL) was added dropwise. After 30 min at –78 ºC, a solution of formaldehyde in
THF (0.37 M, 5.06 mL, 1.62 mmol) was added. After 1 h at –78 ºC, the reaction was allowed to
warm to room temperature, quenched with saturated aq. NH4Cl (5 mL), and partitioned
between cold 2N aq. HCl (15 mL) and diethyl ether (30 mL). Concentration and gradient flash
chromatography (petroleum ether to 40% EtOAc in petroleum ether) afforded Z-enol ester 6 (128
mg, 73.9% yield) as a colorless oil; (IR (film) 3440, 2974, 2934, 1712, 1687, 1442, 1307, 1062 cm-1;
1H NMR (300 MHz, CDCl3)  7.10 (ddd, J = 6.4, 1.3, 1.3 Hz, 1H), 4.76 (dd, J = 13.8, 7.2 Hz, 1H),
4.07 (m, 1H), 3.83 (m, 1H), 3.67 (dd, J = 6.9, 6.6 Hz, 2H), 2.43 (m, 2H), 1.25 (d, J = 5.7 Hz, 12H);
13C{1H} NMR (75 MHz, CDCl3) 153.0, 137.4, 106.8, 62.3, 47.0, 45.9, 28.9, 21.7, 20.5; MS (ESI) m/z
(relative intensity) 216 ([M+H]+, 77%), 333 (27%), 282 (100%); HRMS (ESI-TOF) Calcd. for
C11H21NaNO3 ([M+Na]+): 238.1419, Found: 238.1437.
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7
(Z)-4-(1-Phenyl-1H-tetrazol-5-ylthio)but-1-enyl diisopropylcarbamate (7). To a solution of
6 (51 mg, 0.24 mmol), 1-phenyltetrazol-5-ylthiol (211.1 mg, 1.184 mmol) and triphenylphosphine
(310.8 mg, 1.184 mmol) in THF (1 mL) at 0 ºC was added dropwise a solution of diisopropyl
azodicarboxylate (335.3 mg, 1.658 mmol) in THF (1 mL). After 2 h at room temperature,
concentration and gradient flash chromatography (petroleum ether to 20% EtOAc in petroleum
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ether) afforded sulfide 7 (79 mg, 90% yield) as a colorless viscous oil; IR (film) 2967, 1707, 1497,
1433, 1299, 1077 cm-1; 1H NMR (300 MHz, CDCl3)  7.58-7.52 (m, 5H), 7.12 (ddd, J = 6.3, 1.2, 1.2
Hz, 1H), 4.81 (dd, J = 13.8, 7.2 Hz, 1H), 4.01 (m, 1H), 3.83 (m, 1H), 3.46 (dd, J = 7.2, 6.6 Hz, 2H),
2.74 (m, 2H), 1.21 (d, J = 6.3 Hz, 12H); 13C{1H} NMR (75 MHz,CDCl3)  154.3, 152.6, 137.4, 133.8,
130.3, 130.0, 123.9, 107.1, 46.9, 46.0, 33.1, 24.9, 21.5, 20.5; MS (ESI) m/z (relative intensity) 398
([M+Na]+, 22%), 333 (15%), 282 (100%); HRMS (ESI-TOF) Calcd. for C18H26N5O2S ([M+H]+):
376.1807, Found: 376.1812.
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8
(Z)-4-(1-Phenyl-1H-tetrazol-5-ylsulfonyl)but-1-enyl diisopropylcarbamate (8). To
a
solution of sulfide 7 (27 mg, 0.072 mmol) in ethanol (0.8 mL) at 0 ºC was added a cooled (0 °C)
solution of ammonium molybdate tetrahydrate (17.8 mg, 0.0144 mmol) in 30% aqueous
hydrogen peroxide (1.2 mL, 1.1 mmol). After 12 h at ambient temperature, the reaction mixture
was partitioned between water (5 mL) and EtOAc (25 mL). Concentration and radial
chromatography (20% EtOAc in petroleum ether) afforded sulfone 8 (26.3 mg, 90.7% yield) as a
colorless solid. IR (film) 2973, 2926, 2250, 1707, 1468, 1427, 1345, 1153 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.70-7.64 (m, 2H), 7.63-7.55 (m, 3H), 7.14 (ddd, J = 6.3, 1.5, 1.2 Hz, 1H), 4.75 (m, 1H),
3.96 (m, 2H), 3.79 (m, 2H), 1.24 (d, J = 6.9 Hz, 12H); 13C{1H} NMR (75 MHz, CDCl3) δ 153.5, 152.1,
138.2, 133.1, 131.6, 129.9, 125.2, 104.2, 55.5, 46.9, 46.4, 21.6, 20.5, 18.6; MS (ESI) m/z (relative
intensity) 408 ([M]+, 20%), 430 ([M+Na]+, 45%), 282 (100%); HRMS (ESI-TOF) Calcd. for
C18H26N5O4S ([M+H]+): 408.1706, Found: 408.1717.
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9 (racemic)
3-(2-(1-Phenyl-1H-tetrazol-5-ylsulfonyl)ethyl)oxiran-2-yl diisopropylcarbamate (9). To a
solution of enol ester 8 (26.3 mg, 0.0645 mmol) in acetone (1.5 mL) at –10 ºC was added a solution
of dimethyl dioxirane in acetone (10 mL, prepared from a mixture of acetone, water, sodium
bicarbonate and Oxone). After 5 h at ambient temperature, concentration and radial
chromatography (35% EtOAc in petroleum ether) afforded epoxide 9 (27.3 mg, quantitative
yield) as a colorless oil; IR (film) 2973, 2936, 1710, 1693, 1499, 1433, 1349, 1152 cm-1; 1H NMR (300
MHz, CDCl3)  7.72-7.66 (m, 2H), 7.63-7.56 (m, 3H), 5.63 (d, J = 2.4 Hz, 1H), 3.97-3.80 (m, 4H),
3.20, (m, apparent dt, J = 6.0, 6.0, 2.1 Hz, 1H), 2.49-2.36 (m, 2H), 1.24 (d, 6H), 1.20 (d, 6H); 13C{1H}
NMR (75 MHz, CDCl3)  153.5, 153.4, 133.1, 131.8, 130.0, 125.2, 76.2, 53.7, 53.2, 46.9, 46.5, 21.5;
MS (ESI) m/z (relative intensity) 446 ([M+Na]+, 100%), 279 (36%), 216 (35%); HRMS (ESI-TOF)
Calcd. for C18H26N5O5S ([M+H]+): 424.1655, Found: 424.1662.
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2a (racemic)
5-(3-(tert-Butyldimethylsilyloxy)-4,4-dimethoxybutylsulfonyl)-1-phenyl-1H-tetrazole
(2a). To a solution of epoxide 9 (26 mg, 0.061 mmol) in CH2Cl2 (2 mL) were added 2,6-lutidine
(0.028 mL, 0.12 mmol) and tert-butyldimethylsilyl triflate (0.034 mL, 0.074 mmol) at –10 ºC. After
12 h at ambient temperature, the reaction mixture was partitioned between saturated aq. NH4Cl
and CH2Cl2 (20 mL). Concentration and flash chromatography (petroleum ether/EtOAc)
afforded aldehyde 10 (20 mg, 80% yield) as a colorless oil that was immediately used in the next
step. To a solution of aldehyde 10 (20 mg, 0.049 mmol) in methanol (1.5 mL) were added excess
trimethylorthoformate (0.75 mL) and p-toluenesulfonic acid (1.9 mg, 0.0097 mmol). After 30 min,
the reaction was the reaction mixture was partitioned between saturated aq. NH4Cl and diethyl
ether (25 mL). Concentration and flash chromatography (10% EtOAc in petroleum ether to 40%
EtOAc in petroleum ether) afforded dimethyl acetal 2a (18 mg, 86% yield) as a colorless oil; IR
1
(film) 2930, 2856, 1499, 1463, 1342, 1151 cm-1; H NMR (300 MHz, CDCl3)  7.70-7.64 (m, 2H),
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7.62-7.55 (m, 3H), 4.11 (d, J = 4.8 Hz, 1H), 3.95-3.78 (m, 3H), 3.43 (s, 3H), 3.41 (s, 3H), 2.19-2.12
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(m, 2H), 0.89 (s, 9H), 0.09 (s, 6H); C{1H} NMR (75 MHz, CDCl3)  153.5, 133.2, 131.6, 129.9,
6
7
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9
125.3, 107.5, 71.1, 56.5, 56.3, 52.6, 29.9, 26.0, 25.1, 23.2, 18.3, -4.3, -4.7; HRMS (ESI-TOF) Calcd. for
C19H32N4O5NaSSi ([M+Na]+): 479.1760, Found: 479.1767.
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3-(1-Phenyl-1H-tetrazol-5-ylthio)propanal (14). To a solution of acrolein (0.52 mL, 7.9
mmol) in THF (8 mL) at –78 ºC was added 1-phenyl-1H-tetrazole-5-thiol (1 g, 6 mmol) in THF (2
mL), followed by triethylamine (0.05 mL, 0.3 mmol). The mixture was stirred for 24 h at –5 °C.
Concentration and gradient flash chromatography (petroleum ether to 30% EtOAc in petroleum
ether) afforded 14 (1.26 g, 96.2% yield) as a colorless oil; IR (film) 3063, 2835, 2733, 1723, 1500,
1387 cm-1; H NMR (300 MHz, CDCl3)  9.82 (s, 1H), 7.57-7.55 (m, 5H), 3.62 (t, J = 6.5 Hz, 2H),
1
3.18 (t, J = 6.5 Hz, 2H); 13C{1H} NMR (75 MHz, CDCl3)  199.2, 153.9, 133.5, 130.2, 129.8, 123.7,
43.3, 25.2; MS (ESI) m/z (relative intensity) 235 ([M+H]+, 100%), 257 ([M+Na]+, 100%); HRMS
(ESI-TOF) Calcd. for C10H11N4OS ([M+H]+): 235.0654, Found: 235.0661.
(S)-15a
(S)-4-(1-Phenyl-1H-tetrazol-5-ylthio)-2-hydroxybutanenitrile
((S)-15a).
Cyanation
procedure using (R)-18 and Ti(Oi-Pr)4. A mixture of (R)-1848 (1.29 g, 3.65 mmol) and Ti(Oi-Pr)4
(1.04 g, 3.65 mmol) in CH2Cl2 (50 mL) was stirred for 1 h at room temperature. TMSCN (9.8 mL,
73 mmol) was added at –50 ºC and after 10 min, aldehyde 14 (8.6 g, 37 mmol) in CH2Cl2 (150
mL) was slowly added over 30 min. After 48 h at –50 ºC, aq. HCl (2 N, 400 mL) and EtOAc (200
mL) were added at –50 ºC [CAUTION: hydrogen cyanide may be evolved from acidified
reaction mixtures and extraction fractions; these should be handled in a hood], and the mixture
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was allowed to warm to room temperature. After 3 h, the mixture was extracted with EtOAc
(600 mL). The organic phase was washed with brine and dried over Na2SO4. Concentration and
flash chromatography (8% EtOAc in petroleum ether to 25% EtOAc in petroleum ether) afforded
ligand 18 (92% recovery) and (S)-15a (9.5 g, 99% yield) as a pale yellow oil; IR (film) 3406, 2926,
2249, 1596, 1500, 1414, 1390, 1076 cm-1; 1H NMR (300 MHz, CDCl3)  7.62-7.54 (m, 5H), 4.89 (d, J
= 6.6 Hz, 1H), 4.73 (ddd, J = 8.6, 6.6, 4.1 Hz, 1H), 3.61 (ddd, J = 14.6, 8.6, 5.7 Hz, 1H), 3.52 (ddd, J
= 14.7, 5.9, 5.9 Hz, 1H), 2.49 (dddd, J = 14.4, 8.6, 5.7, 5.6 Hz, 1H), 2.36 (dddd, J = 14.7, 10.3, 6.2,
4.1 Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3)  154.9, 133.4, 130.8, 130.2, 124.1, 119.4, 58.8, 36.1,
28.6; MS (ESI) m/z (relative intensity) 262.04 ([M+H]+, 30%), 235.04 (100%); Anal. Calcd. for
C11H11N5OS: C, 50.56; H, 4.24; N, 26.80. Found: C, 50.90; H, 4.43; N, 26.44. Enantiomer ratio and
optical rotation measurements were made after O-silylation to avoid racemization. This run
furnished material of 82.6%ee. In a separate run using lower temperature and longer reaction
time (–60 °C, 93 h), from aldehyde 14 (0.4568 g, 1.748 mmol) was obtained cyanohydrin (S)-15a
(0.4380 g, 85% yield); these conditions provided material of 97.7%ee.
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(R)-15a
(R)-4-(1-Phenyl-1H-tetrazol-5-ylthio)-2-hydroxybutanenitrile
((R)-15a).
Cyanation
procedure using (S)-18 and Ti(Oi-Pr)4. Using the procedure as described for (S)-15a, from 14
(11.2 g, 47.9 mmol) and ligand (S)-18, was obtained (R)-15a (12.2 g, 97.6% yield); the recovery of
ligand (S)-18 was 71%. Enantiomer ratio and optical rotation measurements were made after
the following step to avoid racemization.
(R)-15b
(R)-2-tert-Butyldimethylsilyloxy-4-(1-phenyl-1H-tetrazol-5-ylthio)butanenitrile
(15b).
Cyanation procedure using Al-Salen catalyst (S,S)-11. To a mixture of (S,S)-11 (36.3 mg, 0.0598
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mmol) and triphenylphoshine oxide (166 mg, 0.598 mmol) in CH2Cl2 (23 mL) was added
aldehyde 14 (1.2 g, 5.98 mmol) in CH2Cl2 (10 mL) at –50 ºC. After 30 min, TMSCN (1.04 mL, 7.77
mmol) was added at –50 ºC. After 20 h at –50 ºC, aq. HCl (2 N, 100 mL) and EtOAc (200 mL)
were added at –50 ºC [CAUTION: hydrogen cyanide may be evolved from acidified reaction
mixtures and extraction fractions; these should be handled in a hood], and the mixture was
allowed to warm to room temperature. After 3 h, the mixture was extracted with EtOAc (600
mL). The organic phase was washed with brine and dried over Na2SO4. Concentration and flash
chromatography (8% EtOAc in petroleum ether to 25% EtOAc in petroleum ether) afforded (R)-
15a (1.1 g, 85% yield) as a pale yellow oil that was immediately subjected to the next step. To a
solution of (R)-15a (115 mg, 0.44 mmol) in CH2Cl2 (3 mL) were added 2,6-lutidine (0.118 mL,
1.01 mmol) and TBSOTf (0.132 mL, 0.572 mmol) at room temperature. After 10 h, the reaction
mixture was partitioned between water (200 mL) and CH2Cl2 (300 mL). The organic phase was
washed with brine and dried over Na2SO4. Concentration and gradient flash chromatography
(petroleum ether to 40% EtOAc in petroleum ether) afforded (R)-15b (139 mg, 84% yield, 50%ee)
as a colorless oil.
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(S)-15b
(S)-2-tert-Butyldimethylsilyloxy-4-(1-phenyl-1H-tetrazol-5-ylthio)-butanenitrile ((S)-15b).
Multigram-scale procedure from cyanohydrin. To a solution of cyanohydrin (S)-15a (9.5 g, 36
mmol) in CH2Cl2 (550 mL) were added imidazole (6.6 g, 91 mmol) and tert-butyldimethylsilyl
chloride (8.7 g, 55 mmol) at room temperature. After 18 h, the reaction mixture was partitioned
between water (200 mL) and CH2Cl2 (300 mL). The organic phase was washed with brine and
dried over Na2SO4. Concentration and gradient flash chromatography (petroleum ether to 40%
EtOAc in petroleum ether) afforded (S)-15b (13.6 g, 98.9% yield, 82.6%ee) as a colorless oil; IR
(film) 2955, 2931, 2886, 2858, 2238, 1500, 1413, 1389, 1255, 1113 cm-1; 1H NMR (300 MHz, CDCl3)
 7.57-7.53 (m, 5H), 4.63 (dd, J = 6.2, 6.1 Hz, 1H), 3.59-3.43 (m, 2H), 2.44-2.37 (m, apparent q, 2H),
0.91 (s, 9H), 0.21 (s, 3H), 0.15 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3)  153.7, 133.7, 130.5, 130.1,
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124.0, 119.3, 60.5, 35.7, 28.3, 25.7, 18.2, –5.0, –5.2; MS (ESI) m/z (relative intensity) 376.10 ([M+H]+,
100%), 398.10 ([M+Na]+, 20%); HRMS (ESI-TOF) Calcd. for C17H26N5OSSi ([M+H]+): 376.1627,
Found: 376.1628. HPLC retention times (Chiralcel OD-H, gradient elution from 0% to 40% i-
PrOH in hexane over 40 min, 1mL/min): tr 21.1 min (minor), tr 22.1 min (major). A sample of
47%ee, obtained in a different run, gave []D24 –17.8 (c 0.455, CHCl3).
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(R)-15b
(R)-2-tert-Butyldimethylsilyloxy-4-(1-phenyl-1H-tetrazol-5-ylthio)-butanenitrile
((R)-
15b). Multigram-scale procedure from cyanohydrin. Using the procedure described for (S)-
15b, from (R)-15a (1.78 g, 6.81 mmol) was obtained (R)-15b (2.54 g, 99.6% yield, 86.0%ee). In a
different run, a sample of 47.3%ee gave []D23 +20.4 (c 0.435, CHCl3).
(S)-1a
(S)-2-tert-Butyldimethylsilyloxy-4-(1-phenyl-1H-tetrazol-5-ylsulfonyl)butanenitrile ((S)-
1a). To a solution of (S)-15b (302 mg, 0.804 mmol) in ethanol (9 mL) at 0 ºC was added a solution
of ammonium molybdate (20 mg, 0.016 mmol) in 30% aq. H2O2 (191 mg, 5.6 mmol). The reaction
mixture was allowed to warm to room temperature. After 24 h, the reaction mixture was diluted
with ethyl acetate (5 mL) and H2O (5 mL), concentrated to remove ethanol, and partitioned
between ethyl acetate and water. The organic phase was washed with brine and dried over
Na2SO4. Concentration and gradient flash chromatography (petroleum ether to 40% EtOAc in
petroleum ether) afforded (S)-1a (311 mg, 95.1% yield) as a colorless solid. Another run on 12 g
scale afforded (S)-1a (11.6 g, 89.2% yield, 83.4%ee) as a colorless solid. Recrystallization from
petroleum ether containing a small amount of ethyl acetate afforded analytically pure sample of
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(S)-1a (6.95 g, >99%ee) as a colorless fluffy mass of very fine needles; mp 69.5–70.5 ºC; []D
–
24.7 (c 0.530, CHCl3); IR (film) 2955, 2932, 2859, 2492, 2361, 1498, 1464, 1344, 1150, 1114 cm-1; 1H
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NMR (300 MHz, CDCl3)  7.71-7.58 (m, 5H), 4.74 (dd, J = 5.8, 5.6 Hz, 1H), 4.03-3.86 (m, 2H), 2.56-
2.48 (m, 2H), 0.93 (s, 9H), 0.23 (s, 3H), 0.18 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3)  131.9, 130.1,
125.2, 118.6, 59.8, 51.6, 29.7, 25.7, 18.3, –5.0, –5.1; MS (ESI) m/z (relative intensity) 407.9 (M+, 55%),
408.9 ([M+H]+, 25%), 215.87 (100%); Anal. Calcd. for C17H25N5O3SSi: C, 50.10; H, 6.18; N, 17.18.
Found: C, 49.96; H, 6.20; N, 17.27. HPLC retention times (Chiralcel OD-H, gradient elution from
0% to 40% i-PrOH in hexane over 40 min, 1 mL/min): tr 27.5 min (minor), tr 29.1 min (major).
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(R)-1a
(R)-2-tert-Butyldimethylsilyloxy-4-(1-phenyl-1H-tetrazol-5-ylsulfonyl)butanenitrile ((R)-
1a). Using the procedure described for (S)-1a, from (R)-15b (10.8 g, 28.8 mmol) was obtained
(R)-1a (10.9 g, 93.2% yield, 86%ee) as a colorless solid. Recrystallization from petroleum ether
containing a small amount of ethyl acetate afforded analytically pure sample of (R)-1a (6.56 g,
>99%ee) as colorless colorless fluffy mass of very fine needles; mp 69.5–70.0 ºC; []D25 +26.6 (c
0.935, CHCl3).
Configurational Assignment of (R)-1a. Configuration of (R)-1a was assigned via NMR using
MPA ester analysis according to the Riguera method.49 After removal of the TBS group (TsOH,
MeOH, H2O, 99%), the resulting cyanohydrin (R)-1c was divided into two portions. Separate
esterifications with (S)- and (R)-methoxyphenylacetic acid in the presence of EDCI and DMAP
led to (R,S) MPA cyanohydrin ester (70% yield) and (R,R) MPA cyanohydrin ester (72% yield).
The pair of diastereomeric MPA cyanohydrin esters were analyzed by proton and carbon NMR
to determine the Δδ(R–S) values. With nitrile carbon numbering (CN = C1), the protons at C3
and C4 exhibited Δδ(R–S) of +0.11 and +0.35, respectively. For the CN carbon, Δδ(R–S) was –
0.25. These data led to conclusive assignment of the (R)-configuration.
2b
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To a solution of racemic nitrile 1a (552 mg, 1.35 mmol) in toluene (22 mL) at –78 ºC was added
DIBALH (1M in toluene, 1.63 mL, 1.63 mmol). After 1 h, the temperature was slowly raised to –
20 ºC over a period of 3 h. The reaction mixture was quenched with ethyl acetate (20 mL) at –20
ºC, and then saturated aqueous sodium potassium tartrate (35 mL) was added. After 24 h, the
mixture was filtered through a Celite pad and the filtrate was extracted with ethyl acetate. The
organic phase was dried over Na2SO4. Concentration and radial chromatography (40% EtOAc
in petroleum ether) afforded unreacted nitrile 1a (148 mg, 27% recovery) and aldehyde 10 (371
mg, 67% yield) as a pale yellow oil; 1H NMR (300 MHz, CDCl3) δ 9.63 (d, J = 0.6 Hz, 1H), 7.68-
7.62 (m, 5H), 4.24 (dd, J = 5.6, 0.6 Hz, 1H), 3.86-3.77 (m, 2H), 2.38- 2.30 (m, 2H), 0.94 (s, 9H), 0.14
(s, 3H), 0.13 (s, 3H). To a solution of aldehyde 10 (49 mg, 0.12 mmol) and triethylorthoformate
(0.8 mL) in ethanol (4 mL) at room temperature was added toluenesulfonic acid (5 mg, 0.02
mmol). After 3 h, the reaction mixture was partitioned between sodium carbonate solution (10
mL) and ethyl acetate, and the organic phase was dried over Na2SO4. Concentration and radial
chromatography (10% EtOAc in petroleum ether) afforded acetal 2b (41 mg, 70% yield) as a
colorless oil. The characterization sample was obtained from another run using enantiomerically
pure (R)-1a. []21D = –1.65 (c = 1.21, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.70-7.66 (m, 2H), 7.63-
7.56 (m, 3H), 4.28 (d, J = 4.8 Hz, 1H), 3.96-3.81 (m, 3H), 3.76-3.47 (m, 4H), 2.27-2.12 (m, 2H), 1.21
(t, J = 7.0 Hz, 6H), 0.90 (s, 9H), 0.09 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3)  154.4, 133.1, 131.4,
129.7, 125.1, 104.8, 71.4, 64.5, 64.2, 52.5, 25.8, 24.9, 18.1, 15.4, 15.2, -4.5, -4.9 ppm; HRMS (ESI-TOF)
Calcd for C21H36N4O5NaSiS ([M+Na]+): 507.2073, Found 507.2076.
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General Procedure A: Julia–Kocienski Reactions. To a solution of the sulfone (1 equiv) in
THF (0.03 M) was added NaHMDS or KHMDS (1 M in THF, 1.2 equiv) at –78 ºC. After 45 min,
the requisite aldehyde (1 equiv) in THF (0.2 M) was added to the reaction mixture at –78 ºC.
After 3 h at –78 ºC, the reaction mixture was quenched with aqueous NH4Cl solution and
allowed to warm to room temperature, then extracted with EtOAc. The organic phase was
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washed with water and brine, then dried over Na2SO4. Concentration and radial
chromatography (2%–7% EtOAc in petroleum ether) afforded the alkene products.
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(E)-tert-Butyl-(1,1-diethoxy-5-phenylpent-4-en-2-yloxy)dimethylsilane (16). From 2b (123
mg, 0.254 mmol) and benzaldehyde (53.9 mg, 0.508 mmol) via General Procedure A was
obtained 16 (78 mg, 84% yield, E/Z >98:2) as a colorless oil. The characterization sample was
obtained from another run using enantiomerically pure (R)-2b. []23D = -1.5 (c = 0.62, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.36-7.16 (m, 5H), 6.42 (d, J = 16.0 Hz, 1H), 6.33-6.25 (m, 1H), 4.28
(d, J = 5.7 Hz, 1H), 3.78-3.65 (m, 3H), 3.64-3.53 (m, 2H), 2.56-2.38 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H),
1.22 (t, J = 7.1 Hz, 3H), 0.90 (m, 9H), 0.08 (s, 3H), 0.05 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) 
137.8, 131.9, 128.4, 127.3, 126.8, 126.8, 125.9, 105.2, 73.7, 64.0, 63.7, 36.6, 25.9, 18.2, 15.4, 15.3, -4.4,
-4.6 ppm; HRMS (ESI-TOF) Calcd for C21H36O3SiNa ([M+Na]+): 387.2331, Found 387.2330. A
fraction enriched in the minor (Z)-isomer was obtained after careful radial chromatography, and
its 1H NMR spectrum showed an olefin peak at  6.50 (J = 11.8 Hz).
(R)-1a: Retention of Configuration
Retention of Configuration in Sulfononitrile (R)-1a under Julia–Kocienski reaction
conditions. To a solution of sulfononitrile (R)-1a (40 mg, 0.098 mmol) of 44% ee (R/S 72:28 by
HPLC) in THF (2 mL) was added NaHMDS (1 M in THF, 0.15 mL, 0.15 mmol) at –78 ºC. After 3
h, the reaction mixture was quenched with water (2 mL) and allowed to warm to room
temperature, then extracted with EtOAc. The organic phase was washed with water, brine, and
then dried over Na2SO4. Concentration and radial chromatography (40% EtOAc in petroleum
ether) afforded pure sulfononitrile (R)-1a (39 mg, 99% yield). Analysis by HPLC (Chiralcel OD-
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H, gradient elution from 0% to 40% i-PrOH in hexane over 40 min, 1 mL/min) showed
enantiomer ratio R/S of 73:27 (46% ee), indicating that no racemization was observed.
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(R,E)-2-tert-Butyldimethylsilyloxy-5-phenylpent-4-enenitrile (17a). From (R)-1a (30 mg,
0.074 mmol) and benzaldehyde (7.8 mg, 0.074 mmol) via General Procedure A was obtained 17a
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2955, 2931, 2886, 2858, 2312, 2230, 1471, 1362, 1255, 1112 cm-1; 1H NMR (300 MHz, CDCl3)  7.36-
7.22 (m, 5H), 6.56 (d, J = 15.9 Hz, 1H), 6.18 (ddd, J = 15.8, 7.3, 7.3 Hz, 1H), 4.50 (dd, J = 6.5, 6.5
Hz, 1H), 2.78-2.65 (m, 2H), 0.92 (s, 9H), 0.20 (s, 3H), 0.15 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3)
 136.9, 135.3, 128.8, 128.0, 126.5, 122.4, 119.9, 62.4, 40.2, 25.8, 18.3, –4.9, –5.0; MS (EI) m/z (relative
intensity) 287.2 (M+, 1%), 230.1 ([M–tBu]+, 80%), 117 (100%); Anal. Calcd. for C17H25NOSi: C,
71.03; H, 8.77; N, 4.87. Found: C, 71.08; H, 8.65; N, 4.81. HPLC retention times (Chiralcel AD-H,
gradient elution from 0% to 40% i-PrOH in hexane over 40 min, 0.5 mL/min): tr 14.0 min (major),
tr 16.1 min (minor).
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(R,E)-2-tert-Butyldimethylsilyloxy-6-methylhept-4-enenitrile (19). From (R)-1a (67.8 mg,
0.166 mmol) and 2-methylpropanal (12 mg, 0.17 mmol) via General Procedure A was obtained
19 (40.5 mg, 95.9% yield, E/Z 95:5) as a colorless liquid; []D24 +18.3 (c 0.300, CHCl3); IR (film)
2958, 2932, 2887, 2860, 2234, 1467, 1363, 1255, 1112 cm-1; 1H NMR (300 MHz, CDCl3)  5.60 (dddd,
J = 15.4, 6.6, 1.1, 1.1 Hz, 1H), 5.34 (dddd, J = 15.4, 7.0, 7.0, 1.3 Hz, 1H), 4.36 (t, J = 6.6 Hz, 1H), 2.44
(m, apparent t, J = 6.9 Hz, 2H), 2.27 (m, 1H), 0.98 (d, J = 6.7 Hz, 6H), 0.90 (s, 9H), 0.17 (s, 3H), 0.12
(s, 3H); 13C{1H} NMR (75 MHz, CDCl3)  143.6, 120.0, 119.5, 62.6, 39.8, 31.3, 25.7, 22.4, 18.3, –4.9,
–4.1; MS (ESI) m/z (relative intensity) 276 ([M+Na]+, 75%). HRMS (EI-TOF) Calcd. for
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