Scalable Regioselective and Stereoselective Synthesis of Functionalized (E)-4-Iodobut-3-en-1-ols: Gram-Scale Total Synthesis of Fungal Decanolides and Derivatives

Article abstract of DOI:10.1021/acs.joc.7b02324

A reliable protocol to synthesize both racemic and chiral (E)-4-iodobut-3-en-1-ols from aldehydes or epoxides, respectively, containing various aromatic and aliphatic substitutions has been established. The utility of these compounds was then demonstrated

Full text of DOI:10.1021/acs.joc.7b02324

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Scalable Regio- and Stereoselective Synthesis of
Functionalized (E)-4-iodobut-3-en-1-ols: Gram-scale
Total Synthesis of Fungal Decanolides and Derivatives
Alexander M. Sherwood, Samuel E. Williamson, Stephanie N.
Johnson, Anil Yilmaz, Victor W. Day, and Thomas E. Prisinzano
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02324 • Publication Date (Web): 22 Dec 2017
Downloaded from http://pubs.acs.org on December 22, 2017
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The Journal of Organic Chemistry
Scalable Regio- and Stereoselective Synthesis of Functionalized (E)-4-iodobut-3-
en-1-ols: Gram-scale Total Synthesis of Fungal Decanolides and Derivatives
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Alexander M. Sherwood, Samuel E. Williamson, Stephanie N. Johnson, Anil Yilmaz, Victor W. Day
and Thomas E. Prisinzano*
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Department of Medicinal Chemistry, School of Pharmacy, The University of Kansas, Lawrence, KS,
USA.
Abstract
A reliable protocol to synthesize both racemic and chiral (E)-4-iodobut-3-en-1-ols from aldehydes or
epoxides, respectively, containing various aromatic and aliphatic substitutions has been established.
The utility of these compounds was then demonstrated by providing access to known fungal
decanolides as well as novel aromatic macrocycles. The protocol provided a gram scale route to (–)-
aspinolide A and (–)-5-epi-aspinolide A utilizing a catalytic Nozaki-Hiyama-Kishi reaction to close the
macrolide in the final step in 65-84% yield.
R
Br
+
O
H
O
3 - steps
R
4 - steps
O
-or-
I
*
OH
5
R
HO
R
+
*
O
Li
15 examples
Aspinolide A
5-epi-Aspinolide A
+ others
up to 95 % yield
R =
aryl, heteroaryl, alkyl
gram scale, > 60 %
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1
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Nature has provided a variety of compounds bearing the structural motif illustrated by 1 (Figure 1),
including the anti-tumor compound, rugulactone (2) as well as a diverse array of unsaturated
macrolide natural products (3-5) with an array of biological activities, several of which are illustrated in
Figure 1.1-5 We envisaged that hydroxy vinyl iodides (6) could provide viable synthons for producing
molecules related to 1-5.
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Esterification
O
H
O
O
R2
OH
I
R3
R1
R
1
6
NHK
O
O
O
O
O
2
HO
Me
3
O
O
O
HO
HO
HO
Me
O
O
4
Me
5
Figure 1. Design rationale for structures of natural products containing hydroxy
vinyl core (1): rugulactone (2), aspinolide A (3), pochonin F (4), and aigialomycin
D (5).
One of the key challenges in synthesizing macrocyclic lactones such as 3-5 is the ring-closing
step, which must overcome challenging kinetic and thermodynamic barriers to succeed.6,7 Several
methods have been previously reported for synthesizing macrocyclic lactones employing ruthenium
catalyzed metathesis (RCM) in the final ring closing step.8,9 The major drawbacks to macrocycle
formation using RCM are the necessary judicious optimization of reaction conditions as well as the
challenge in controlling the double bond geometry.10 In search of a more general method to form
macrocyclic lactones containing double bonds, the current literature was surveyed for alternative
approaches. Of the available methods for closing strained medium to large rings containing double
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bonds to form allylic alcohols or enones with the preservation of double bond geometry, the nickel-
chromium mediated Nozaki-Hiyama-Kishi (NHK) coupling reaction has emerged as one of the more
viable methods by demonstrating good functional group tolerance, scalability, and its remarkable
ability to close strained rings preferentially over forming dimers.11-13 Furthermore, environmentally
favorable catalytic variants of the NHK reaction have been subsequently realized which utilize
stoichiometric manganese, allowing the chromium content of the reaction to be reduced to catalytic
amounts.14-16
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Requisite to forming an allylic alcohol-bearing macrocycle (7) by NHK conditions is a vinyl iodide
tethered aldehyde (8, Figure 2). With the goal of taking advantage of the merits of the NHK reaction
as a potential route to nature-inspired macrolides via the approach illustrated in Figure 2, a general
route to (E)-4-iodobut-3-en-1-ols (6) was desired.
OH
R
O
R
I
O
H
O
NHK
O
O
7
8
Figure 2. General approach to macrocyclic allylic alcohols.
Hydrozirconated intermediates have proven to be particularly useful for the formation of vinyl
iodides. Hydrozirconation of terminal alkynes by Schwartz’s reagent (Cp2Zr(H)Cl) has been
previously utilized in synthetic organic chemistry for several reasons, including the reagent’s
acceptance of mild conditions, efficiency, commercial availability, and excellent regiocontrol.17
Furthermore, despite some reports of the reagent’s inherent sensitivity, in our hands, handling
Schwartz's reagent in open air had no apparent ill effect on subsequent transformations and the
purchased container of Schwartz’s reagent was found to retain complete activity after a year,
provided the container was blanketed with argon after each use and stored away from light under
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refrigeration. In addition to commercial availability, the reagent can also be prepared from
inexpensive Cp2ZrCl2 and LiAlH4.18 Despite these advantageous utilities, other methods for vinyl
iodide synthesis from alkynes remain popular, including hydrohalogenation,19 hydrostannation,20
hydroboration,21 and hydroalumination.20 Of these methods, our initial experiments to synthesize 6a
revealed Schwartz’s reagent to be a good choice with a broad substrate scope and operationally
simple experimental design.
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Table 1 illustrates a variety of hydroxy vinyl iodides (6) accessed from triethylsilyl protected
homopropargyl alcohols (12). An array of racemic homopropargyl alcohols (11) were synthesized
using operationally simple (open air) Barbier conditions with the corresponding aldehydes and
propargyl bromide.22 Though Schwartz’s reagent has been reported to tolerate free alcohols,23 initial
efforts to form 6 directly from the homopropargyl alcohols were unfruitful; when the same conditions
were applied to the alcohols protected as triethylsilyl ethers, the hydrozirconation reactions
proceeded with quantitative yield in most cases. Additionally, it was found that adding a catalytic
amount of DMAP to the silylation reactions significantly enhanced reaction rates24 and afforded the
protected alcohols in minutes from homopropargyl alcohols, typically in quantitative yield. Curiously,
without catalytic DMAP, the silylations typically had to stir overnight and sometimes did not reach
completion. Finally, we were pleased to find that the triethylsilyl ethers were cleanly hydrolyzed by
quenching the final reaction with dilute acid affording the hydroxy vinyl iodides (6) in one pot.
Table 1. Scope of hydroxy vinyl iodide synthesis
via racemic homopropargyl alcohols.
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R1
R1
Zn, Et2O/DMF
1-12h, rt.
Br
+
1
2
3
H
O
OR2
11:R2 = H
9
10
ClSiEt3, imidazole
DMAP, CH2Cl2,
30 min, rt.
12:R2 = SiEt3
4
5
R1
1. Cp2Zr(H)Cl, CH2Cl2, 1h, 0 °C - rt
2. N-iodosuccinimide, THF, 1h, 0 °C - rt
I
OH
3. 6N HCl, 45 min, 0 °C
6
7
8
6
yield (%)a
12
entry
R1
11
6
9
11a
94
12a
97
6a
92
1
2
10
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OMe
11b
90
12b
99
6b
83
OMe
11c
99
12c
99
6c
98
3
4
5
OMe
MeO
OMe
11d
70
12d
72
6d
95
CF3
11e
70
12e
87
6e
90
F
11f
75
12f
77
6f
6
7
8
74
11g
79
12g
95
6g
97
F
CN
11h
85
12h
91
6h
--c
11i
65
12i
97
6i
N
9
46
O
11j
94
12j
96
6j
10
11
93
11k
72
12k
99
6k
91
S
11l
70
12l
93
6l
12
94
11m
n/ab
12m
97
6m
95
Me
13
14
11n
46
12n
99
6n
99
11o
61
12o
95
6o
96
15
a
b
c
Isolated yield.
11m was commercially available.
Hydrozirconation led to competitive reduction of nitrile
resulting in an intractable mixture of compounds.
Hydrozirconation of the protected homopropargyl alcohols 12a-o was accomplished in
methylene chloride with Schwartz’s reagent in slight excess. The hydrozirconation step was found to
be moisture sensitive; in reactions where environmental moisture was not carefully excluded, a major
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competing reaction led to reduction of the alkyne to the terminal alkene 13 (Figure 3), which was
generally unresolvable by chromatography and can be seen as a trace impurity in the proton NMR
spectra of several products. It was found that the terminal olefin formation could be suppressed
significantly by azeotroping the protected homopropargyl alcohols from toluene or benzene
immediately before use. Iodosuccinimide was implemented instead of elemental iodine for the
iodination step, as it is generally easier to handle and may not produce strongly acidic byproducts.
Additionally, siloxane byproducts from the final deprotection step were often pervasive in initial NMR
spectra. It was found that they could be azeotropically removed from the final products by using
toluene.
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Figure 3. H NMR spectra showing vinyl iodide and minor terminal olefin signals resulting from the
inclusion of trace moisture in hydrozirconation reaction.
Next, we sought to develop a general asymmetric approach to hydroxy vinyl iodides that could be
applied to the synthesis of natural products and derivatives. It is known that homopropargyl alcohols
are also readily accessible by the action of lithium acetylide ethylene diamine complex on terminal
epoxides.43 Furthermore, enantiopure terminal epoxides (15) are often either commercially available
or accessible by straightforward chemistry.
Four representative vinyl iodides from Table 1, 6a, 6b, 6j, and 6m, incorporating aryl, heteroaryl
and alkyl substituents, were selected to demonstrate the general asymmetric approach (Table 2).
While styrene oxide (15a) and propylene oxide (15m) were commercially available in enantiopure
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form, the 3-methoxyphenyl and furan-bearing epoxides, 15b and 15j, have not been previously
described. Likewise, the a-bromoketone 14b was commercially available and the analogous novel
compound 14j was synthesized in three steps from 3-furancarboxaldehyde (10j). Both a-
bromoketones 14b and 14j were then asymmetrically reduced using Ortiz-Marciales et al.’s recently
described25 air-stable spiroborate catalyst and subsequently cyclized under alkaline conditions to give
chiral epoxides 15b and 15j in excellent yield and enantiomeric excess (inferred from chiral GC or
HPLC analysis of either vinyl iodides 6 or the corresponding homopropargyl alcohols 11). The crude
epoxides were reacted with lithium acetylide ethylenediamine complex and the resulting highly
enantioenriched homopropargyl alcohols were reacted as previously described to afford
enantioenriched vinyl iodides 6. This entire sequence was operationally simple, typically requiring
only one chromatographic step from the a-bromoketones to protected homopropargyl alcohols 12.
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Table 2. General approach to chiral hydroxyl
vinyl iodides
Ph
Ph
1.
O
B
O
O
N
H
R1
R1
R1
1. MeMgBr, THF
2. IBX, DMSO
BH3•DMS
O
H
C
O
3. CuBr2,
EtOAc/ CHCl3
(1 column)
O
2. NaOH
Br
10
15
14
HC
Li
H2N
1. Cp2Zr(H)Cl, CH2Cl2
2. N-iodosuccinimide, THF
R1
R1
NH2
DMSO
I
OR2
OH
3. 6N HCl
R/S-11:R2 = H
R/S-6
ClSiEt3, imidazole
DMAP, CH2Cl2,
30 min, rt.
R/S-12:R2 = SiEt3
Yield (%)
ee (%)
entry
R1
14
15
R/S-12
R/S-6
1
15a
coma
(S)12a
95c
(S)6a
88
(S)6a
98e
--
OMe
2
14b
15b
n/ab
(S)12b
89d
(S)6b
93
(S)6b
98e
com
a
O
3
4
14j
73
15j
n/ab
(S)12j
82d
(S)6j
80
(S)11j
97f
Me
15m
coma
(R)12m
67c
(R)6m
96
(R)6m
99f
--
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a
b
intermediate was commercially available. not isolated,
used immediately without further purification or
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2
3
4
c
characterization. isolated yield over two steps from 15. d
isolated yield over three steps from 14. enantiomeric excess
e
determined by chiral HPLC AUC analysis. f enantiomeric
excess determined by chiral GC AUC analysis.
5
6
7
8
9
Finally, both (S)-6a and (R)-6m were used to construct the vinyl iodide tethered aldehyde
intermediates 19 and 20 in three steps which subsequently underwent a ligand-supported catalytic
variant of the NHK reaction, recently described by Tagami et al.,16 to afford decanolide natural
product (–)-aspinolide A (3a) and the corresponding epimer (–)-5-epi-aspinolide A (3b) as well as the
novel macrocycles 21a and 21b (Scheme 1). Though the final ring-closing step was not
diastereoselective, the epimers were readily separated by chromatography. The absolute
stereochemistries of the macrocycles were confirmed by the X-ray structure of 21a and 21b (Figure
4). The configurations for 3a were assigned based on spectroscopic agreement with previous reports
for aspinolide A.2
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Scheme 1. Vinyl iodide-mediated macrolide synthesis. Yield ranges reported for reactions over
multiple trials.
O
OPMB
O
DCC, DMAP
CH2Cl2, rt, 12h
(S)-6a
or
(R)-6m
PMBO
O
+
I
(95 - 99 %)
R
OH
16
17: R = Me
18: R = Ph
O
1. DDQ, phospate buffer, CH2Cl2
2. DMP, NaHCO3, CH2Cl2
O
O
I
(85 - 92 %, 2-steps)
R
19: R = Me
20: R = Ph
4,4’-di-t-Bu-2,2'-bipyridyl
CrCl3 (cat.), Mn0
O
O
O
O
Ni-neocuproine complex
+
Cp2ZrCl2, THF
HO
R
HO
R
(65 - 84 %)
3a: R = Me
21a: R = Ph
3b: R = Me
21b: R = Ph
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Figure 4. X-ray crystal structures for 21a (left) and 21b (right).
1
2
3
4
5
6
7
8
9
Unexpectedly, the NMR data for epimer 3b did not agree with previously reported data for the
matching structure claimed to be the natural product stagonolide F.1 Even more surprising, three
subsequent total synthesis attempts at this natural product that, upon close inspection of the
corresponding supporting information files, provided spectra which neither agreed with the isolation
report nor our spectra for 3b40- 42 (See Supporting Information Fig. S2, Tables S1-S6) In light of
these apparent discrepancies, the following data provided additional support for the structural
assignment of 3b and may suggest the need for structural revision of the compound previously
described as stagonolide F: the highly analogous nature of the chemistry and chromatography used
to synthesize and isolate 3a/b compared to 21a/b, which were unambiguously described by x-ray
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1
structure; comparison of the H NMR spectra for 3a/b demonstrated closely related compounds,
highly indicative of epimers, with key proton shifts that occurred primarily at the proposed region of
epimerization at C5 (See Supporting Information Fig. S1); the HRMS data for 3a/b was identical
and corresponded to the expected values, and chromatographically, the two compounds had very
close Rf values by TLC, thus ruling out the possibility of 3b being a dimer. Analysis of the carbon
NMR data in the original isolation report for stagonolide F1 revealed several unexpectedly significant
divergences in the spectra when compared against spectra for what should have been its C5 epimer,
aspinolide A (and our matching spectra for 3a). Namely, in the 13C NMR for stagonolide F and
aspinolide A, C-8 signals were observed at δ 35.0 and 42.1, respectively. Also, C-3 signals for these
two molecules were observed at δ 31.5 and 22.3, respectively. The different alpha/beta
configurations of hydroxy and methyl groups would not be expected to change the chemical shifts of
20
carbon atoms that much. Finally, our measured optical rotation of 3b, [a]D −62.0 ° (c 0.1, CHCl3),
20
was not in agreement with the reported rotation of stagonolide F, [a]D −27 ° (c 0.1, CHCl3).1 In light
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of the above, compound 3b has been described as (–)-5-epi-aspinolide A instead of stagonolide F in
1
2
3
this manuscript.
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Conclusion
In summary, we have developed a general protocol for the synthesis of (E)-4-iodobut-3-en-1-ols
and explored their utility towards the synthesis of 10-membered macrocycles, both natural and
nature-inspired. We envision that the described protocols will be of utility in future natural product
total synthesis efforts as well as for the exploration of derivatives in structure-activity efforts to
discover novel medicines.
Experimental Section
General Information. All chemical reagents were purchased from commercial suppliers and used
without further purification. Unless mentioned otherwise, all solvents were obtained from a solvent
purification system in which solvent was passed through two columns of activated alumina under
argon. Reactions performed in standard glassware were performed under an atmosphere of argon
using glassware dried overnight in an oven at 120 °C and cooled under a stream of argon unless
specified otherwise. Reactions were monitored by thin-layer chromatography (TLC) on 0.25 mm
Analtech GHLF silica gel plates and visualized using a UV Lamp (254 nm) and vanillin solution (7.5 g
vanillin dissolved in 125 mL EtOH and 1-2 mL H2SO4). Flash column chromatography was performed
on silica gel (4-63 mm) from Sorbent Technologies. Optical rotations were measured on a Rudolph
Autopol III automatic polarimeter. H and 13C NMR were recorded a 500 MHz Bruker AVIII
1
spectrometer equipped with a cryogenically-cooled carbon observe probe using tetramethylsilane as
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an internal standard. Chemical shifts (δ) are reported in ppm and coupling constants (J) are reported
in Hz. High-resolution mass spectrum (HRMS) was performed on a LCT Premier (Micromass Ltd.,
Manchester UK) time of flight mass spectrometer with an electrospray ion source in either positive or
negative mode. Melting points were measured with a Thomas Capillary Melting Point Apparatus and
are uncorrected.
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Zinc activation procedure. 50 g of zinc powder was suspended in 350 mL water in a 500 mL
Erlenmeyer flask. 5 mL concentrated HCl was added dropwise and the suspension stirred for 30
minutes. The suspension was then decanted and the zinc was sequentially washed with water (3 x
100mL), acetone (3 x 100mL) and ether (2 x 50mL). The activated zinc powder was then dried in
vacuo and stored under argon and used within one week.
R1
I
OH
Procedure A: General procedure for the synthesis of (E)-4-iodobut-3-en-1-ols (6). A flame-dried
RBF was charged with Cp2Zr(H)Cl (774 mg, 3.0 mmol) then sealed with a rubber septum and purged
with argon. The solid was suspended in CH2Cl2 (10 mL) and cooled with an external ice bath. Alkyne
(2.0 mmol, previously azeotroped from toluene or benzene x 3) in CH2Cl2 (10 mL) was added
dropwise to the rapidly stirring suspension. The reaction was removed from the ice bath, stirred in
the dark and reached room temperature over one hour. The resulting pale yellow-to-orange solution
was cooled by an external ice bath and iodosuccinimide (562 mg, 2.5 mmol) in THF (10 mL) was
added dropwise. The reaction was removed from the ice bath, stirred in the dark and reached room
temperature over one hour. The resulting orange solution was cooled by external ice bath and HCl
(6M, 1.5 mL, 9.0 mmol) was added dropwise. The reaction was stirred for 45 minutes at 0°C then
poured into a stirring solution of 1:1 saturated aqueous NaHCO3 and Na2S2O3 (50 mL). Vigorous
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stirring continued for 30 minutes resulting in a pale yellow biphasic solution. Et2O (30 mL) was added
and the organic layer was collected. The aqueous layer was further extracted with Et2O (2 x 30 mL).
Combined organic extracts were washed with brine and dried over MgSO4. The solvent was
removed under reduced pressure and the residue was azeotroped from toluene (x3) to remove
siloxane byproducts. Finally, purification via flash column chromatography (2.5-40% EtOAc/hexanes)
afforded vinyl iodides.
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R1
OH
Procedure B: General procedure for the synthesis of homopropargyl alcohols (11) from
propargyl bromide and substituted aldehydes. To a 250 mL RBF fitted with a reflux condenser
was added aldehyde 10 (10 mmol) in 1:1 ether/DMF (100 mL, tech. grade, not anhydrous) and a
solution of 80% propargyl bromide (9) in toluene (1.5 mL, 13 mmol). Activated zinc powder (2.0 g, 30
mmol) was then added portion wise over 10 minutes (Caution: very freshly activated zinc can produce
very exothermic reactions). The reaction was allowed to stir at room temperature for up to 12 hours
with progress monitored by TLC (homopropargyl alcohols typically have Rf: 0.3~0.6 in 100 % CH2Cl2
and stain deep burgundy with vanillin stain). Upon completion, the reaction was slowly quenched with
saturated ammonium chloride and allowed to stir for 30 minutes. The resulting mixture was decanted
into a separatory funnel and the organic layer was separated, the aqueous layer extracted with ether
(3 x 50mL) and the combined organic layers washed with brine (3 x 75mL), dried with MgSO4, and
concentrated in vacuo. The resulting crude product was purified via flash column chromatography to
give homopropargyl alcohols (11).
R1
OSiEt3
Procedure C: General procedure for the synthesis of triethylsilyl ethers (12) from
homopropargyl alcohols.
To a stirred solution of homopropargyl alcohol 11 (3.0 mmol) in
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The Journal of Organic Chemistry
methylene chloride (20 mL) was added imidazole (0.30 g, 4.5 mmol) and DMAP (37 mg, 0.30 mmol).
Once all solids were dissolved, chlorotriethylsilane (0.51 mL, 3.0 mmol) was added dropwise, and the
reaction was allowed to stir at room temperature for 30 minutes. The reaction was quenched with
saturated ammonium chloride and extracted with Et2O (3 x 25 mL). The organic layers were
combined, washed with brine (25mL), dried with MgSO4 and concentrated to give the corresponding
homopropargyl triethylsilyl ether that was used in the next step without further purification.
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R1
OH
Procedure D: General procedure for the synthesis of asymmetric homopropargyl alcohols
a
(R/S-11) from -bromoketones via epoxide intermediate. To a stirred solution of (R)-spiroboronate
ester catalyst24 (171 mg, 0.53 mmol) in 15 mL THF was added BH3•DMS complex (2M in THF, 1.8
mL, 3.7 mmol) at room temperature and stirred for 10 minutes until the cloudy suspension became
clear. A solution of a-bromoketone (14b or 14j, 10 mmol) in 10 mL THF was added via syringe pump
over one hour and allowed to stir an additional 10 minutes after addition was complete. Reaction was
cooled to 0°C and quenched with 10 mL methanol. Volatiles were removed and the residue was
taken up in THF (20 mL) and 2M NaOH (10 mL) and stirred at room temperature for 15 minutes. The
reaction was extracted with Et2O (3 x 25 mL) and the combined organic layers washed with brine (1 x
50 mL), dried (MgSO4) and concentrated. The crude epoxide residue was immediately taken up in
anhydrous DMSO (5 mL) and the solution added dropwise to a stirred solution of lithium acetylide-
ethylene diamine complex (1.47 g, 16.0 mmol) in anhydrous DMSO (15 mL) at room temperature.
The reaction was allowed to proceed overnight at room temperature, at which point it was cooled to
0°C and carefully quenched by the addition of saturated aqueous ammonium chloride solution (20
mL). The resulting solution was extracted with ether (5 x 30 mL), washed with brine (3 x 50 mL), dried
(MgSO4) and concentrated.
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R1
1
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OH
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Procedure E: General procedure for the synthesis of asymmetric homopropargyl alcohols
(R/S-11) from epoxides. A solution of commercially available epoxide (15a or 15m, 1 eq.) in
anhydrous DMSO (2 mmol / mL) was added dropwise to a stirred solution of lithium acetylide-
ethylene diamine complex (1.6 eq.) in anhydrous DMSO (1 mmol / mL) at room temperature. The
resulting exothermic reaction was allowed to proceed overnight at room temperature, at which point it
was cooled to 0°C and carefully quenched by the addition of saturated aqueous ammonium chloride
solution. The resulting solution was extracted with ether (20 mL x 3), washed with brine (20 mL x 3),
dried (MgSO4) and concentrated. The resulting homopropargyl alcohols were typically used without
further purification.
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1-phenylbut-3-yn-1-ol (11a) Prepared according to general procedure B from benzaldehyde (1.06 g,
10 mmol); purified by column chromatography (20% EtOAc/hexane) to give 1.42 g light yellow,
viscous oil, 94%. The spectra were in accordance with the previously reported data.26
(S)-1-phenylbut-3-yn-1-ol [(S)11a] Prepared according to general procedure D from commercially
available (R)-styrene oxide (1.20 g, 10 mmol) to give 1.35 g clear oil, 93%. All spectra were identical
to that of racemic 11a. [a]D20 -25.72° (c. 0.90 , CHCl3){lit27 [a]D20 -14.5 (c. 4.11, MeOH)}.
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The Journal of Organic Chemistry
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1-(3-methoxyphenyl)but-3-yn-1-ol (11b) Prepared according to general procedure B from m-
anisaldehyde (1.36 g, 10 mmol); purified by column chromatography (20% EtOAc/hexane) to give 1.6
g light yellow, viscous oil, 90%. The spectra were in accordance with the previously reported data.28
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(S)-1-(3-methoxyphenyl)but-3-yn-1-ol [(S)11b] Prepared according to general procedure E from
commercially available 2-bromo-1-(3-methoxyphenyl)ethan-1-one 14b (2.29 g, 10 mmol) to give 1.25
20
g clear oil, 71% over two steps. All spectra were identical to that of racemic 11b. [a]D -45.49° (c.
1.09, CHCl3).
1-(4-methoxyphenyl)but-3-yn-1-ol (11c) Prepared according to general procedure B from p-
anisaldehyde (1.36 g, 10 mmol); purified by column chromatography (20% EtOAc/hexane) to give
1.69 g light yellow, viscous oil, 99%. The spectra were in accordance with the previously reported
data.29
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1-(3,4,5-trimethoxyphenyl)but-3-yn-1-ol (11d) Prepared according to general procedure B from
3,4,5-trimethoxybenzaldehyde (2.36 g, 10 mmol); purified by column chromatography (30-40%
EtOAc/hexane) to give 1.68 g white solid (m.p. 62-65 °C), 70%. The spectra were in accordance with
the previously reported data.30
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1-(4-(trifluoromethyl)phenyl)but-3-yn-1-ol (11e) Prepared according to general procedure B from 4-
(trifluoromethyl)benzaldehyde (1.74 g, 10 mmol); purified by column chromatography (20%
EtOAc/hexane) to give 1.50 g white crystalline solid (m.p. 34-36 °C), 70%. The spectra were in
accordance with the previously reported data.31
1-(4-fluorophenyl)but-3-yn-1-ol (11f) Prepared according to general procedure B from 4-
fluorobenzaldehyde (1.24 g, 10 mmol); purified by column chromatography (20% EtOAc/hexane) to
give 1.23 g light yellow, viscous oil, 75%. The spectra were in accordance with the previously
reported data.32
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The Journal of Organic Chemistry
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1-(2-fluorophenyl)but-3-yn-1-ol (11g) Prepared according to general procedure B from 2-
fluorobenzaldehyde (1.24 g, 10 mmol); purified by column chromatography (20% EtOAc/hexane) to
give 1.33 g light yellow, viscous oil, 79%. The spectra were in accordance with the previously
reported data.30
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4-(1-hydroxybut-3-yn-1-yl)benzonitrile (11h) Prepared according to general procedure B from 4-
cyanobenzaldehyde (1.31 g, 10 mmol); purified by column chromatography (20% EtOAc/hexane) to
give 1.52 g light yellow crystalline solid (m.p. 106-108 °C), 85%. The spectra were in accordance with
the previously reported data.31
1-(pyridin-2-yl)but-3-yn-1-ol (11i) Prepared according to general procedure B from 2-
pyridinecarboxaldehyde (1.07 g, 10 mmol); purified by column chromatography (20% EtOAc/hexane)
to give 1.04 g purple, viscous oil, 65%. The spectra were in accordance with the previously reported
data.32
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1-(furan-3-yl)but-3-yn-1-ol (11j) Prepared according to general procedure B from 3-furaldehyde (961
mg, 10 mmol); purified by column chromatography (20% EtOAc/hexane) to give 1.33 g light yellow,
viscous oil, 94%. The spectra were in accordance with the previously reported data.26,33
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(S)-1-(furan-3-yl)but-3-yn-1-ol [(S)11j] Prepared according to general procedure E from 14j (1.9 g,
10 mmol). The resulting orange oil was purified by column chromatography (10-15% EtOAc/Pentane)
20
to give 1.2 g light yellow oil, 86% over two steps. Spectra were identical to that of racemic 11j. [a]D
-
25.6° (c. 1.02, CHCl3) {lit33 -23.7° (c. 1.25, CH2Cl2)}.
1-(thiophen-2-yl)but-3-yn-1-ol (11k) Prepared according to general procedure B from 2-
thiophenecarboxaldehyde (1.12 g, 10 mmol); purified by column chromatography (5-15%
EtOAc/hexane) to give 1.13 g colorless, viscous oil, 72%. The spectra were in accordance with the
previously reported data.28
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The Journal of Organic Chemistry
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1-cyclohexylbut-3-yn-1-ol
(11l)
Prepared according to general procedure
B
from
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cyclohexanecarboxaldehyde (1.12 g, 10 mmol); purified by column chromatography (20%
EtOAc/hexane) to give 1.11 g colorless, viscous oil, 70%. The spectra were in accordance with the
previously reported data.26,29
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(R)-pent-4-yn-2-ol [(R)11m] Prepared according to general procedure D from commercially available
(R)-propylene oxide (10.9 g, 188 mmol) and lithium acetylide-ethylene diamine complex (25 g, 270
mmol) in DMSO (200 mL). Crude product was used in the next step without further purification.
Spectra were identical to that of commercially available racemic 4-pentyn-2-ol. [a]D20 -21.3° (c. 1.01 ,
CHCl3){lit34 [a]D20 -17.7° (c. 0.13 , CHCl3)}.
2,2-dimethylhex-5-yn-3-ol
(11n) Prepared according to general procedure
B
from
trimethylacetaldehyde (863 mg, 10 mmol); purified by column chromatography (0-10%
EtOAc/hexane) to give 583 mg colorless, viscous oil, 46%. The spectra were in accordance with the
previously reported data.35
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dec-1-yn-4-ol (11o) Prepared according to general procedure B from hexanal (1.0 g, 10 mmol);
purified by column chromatography (0-10% EtOAc/hexane) to give 860 mg colorless, viscous oil,
61%. The spectra were in accordance with the previously reported data.36
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triethyl((1-phenylbut-3-yn-1-yl)oxy)silane (12a) Prepared according to general procedure C from
1
11a (438 mg, 3 mmol) to give 760 mg colorless oil, 97%: H NMR (500 MHz, CDCl3) δ 7.34 – 7.26
(m, 2H), 7.29 – 7.15 (m, 3H), 4.74 (t, J = 6.4 Hz, 1H), 2.54 (dddd, J = 16.6, 6.8, 2.7, 0.8 Hz, 1H), 2.48
– 2.39 (m, 1H), 1.88 (t, J = 2.6 Hz, 1H), 0.86 – 0.77 (m, 9H), 0.48 (dtd, J = 16.1, 7.8, 6.8 Hz, 6H); 13C
NMR (126 MHz, CDCl3) δ 144.0, 128.1, 127.5, 125.9, 81.5, 73.5, 70.0, 30.9, 6.8, 4.8. HRMS (ESI):
m/z [M + Na]+ calcd for C16H24OSiNa+: 283.1489; found: 283.1490.
(S)-triethyl((1-phenylbut-3-yn-1-yl)oxy)silane [(S)12a] Prepared according to general procedure C
from (S)11a (1.30 g, 8.9 mmol) to give 2.27 g clear oil, 98%: All spectra were identical to that of
racemic 12a. [a]D20 -32.29° (c. 1.39 , CHCl3).
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The Journal of Organic Chemistry
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triethyl((1-(3-methoxyphenyl)but-3-yn-1-yl)oxy)silane (12b) Prepared according to general
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procedure C from 11b (528 mg, 3 mmol) to give 871 mg light yellow oil, 99%: H NMR (500 MHz,
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CDCl3) δ 7.16 (t, J = 7.9 Hz, 1H), 6.90 – 6.84 (m, 2H), 6.73 (ddd, J = 8.2, 2.7, 1.1 Hz, 1H), 4.76 –
4.68 (m, 1H), 3.74 (s, 3H), 2.53 (ddd, J = 16.7, 6.9, 2.7 Hz, 1H), 2.43 (ddd, J = 16.6, 6.0, 2.7 Hz, 1H),
13
1.90 (t, J = 2.7 Hz, 1H), 0.83 (t, J = 7.9 Hz, 9H), 0.56 – 0.42 (m, 6H); C NMR (126 MHz, CDCl3) δ
159.4, 145.7, 129.0, 118.3, 113.0, 111.3, 81.5, 73.4, 70.0, 55.2, 30.9, 6.8, 4.8. HRMS (ESI): m/z [M +
Na]+ calcd for C17H26O2SiNa+: 313.1594; found: 313.1575.
(S)-triethyl((1-(3-methoxyphenyl)but-3-yn-1-yl)oxy)silane [(S)12b] Prepared according to general
procedure C from (S)11b (1.6 g, 9.1 mmol) to give 2.54 g clear oil, 96%: Spectra were identical to that
of racemic 12b. [a]D20 -37.7° (c. 0.95 , CHCl3).
triethyl((1-(4-methoxyphenyl)but-3-yn-1-yl)oxy)silane (12c) Prepared according to general
1
procedure C from 11c (528 mg, 3 mmol) to give 843 mg colorless oil, 99%: H NMR (500 MHz,
CDCl3) δ 7.33 – 7.29 (m, 2H), 6.92 – 6.85 (m, 2H), 4.79 (t, J = 6.5 Hz, 1H), 3.83 (s, 3H), 2.62 (ddd, J
= 16.6, 6.7, 2.7 Hz, 1H), 2.50 (ddd, J = 16.6, 6.4, 2.7 Hz, 1H), 1.97 (t, J = 2.6 Hz, 1H), 0.91 (t, J = 7.9
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13
Hz, 9H), 0.67 – 0.49 (m, 6H); C NMR (126 MHz, CDCl3) δ 158.9, 136.2, 127.1, 113.4, 81.7, 73.1,
69.9, 55.2, 31.0, 6.8, 4.8. HRMS (ESI): m/z [M + Na]+ calcd for C17H26O2SiNa+: 313.1594; found:
313.1564.
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triethyl((1-(3,4,5-trimethoxyphenyl)but-3-yn-1-yl)oxy)silane (12d) Prepared according to general
1
procedure C from 11d (829 mg, 3 mmol) to give 850 mg colorless oil, 72%: H NMR (500 MHz,
CDCl3) (major rotamer reported) δ 6.54 (s, 2H), 4.69 (dd, J = 6.8, 6.0 Hz, 1H), 3.78 (s, 9H), 2.55 –
2.37 (m, 2H), 1.92 (t, J = 2.6 Hz, 1H), 0.85 (t, J = 7.9 Hz, 9H), 0.53 (qd, J = 7.9, 2.3 Hz, 6H); 13C NMR
(126 MHz, CDCl3) δ 153.0, 139.8, 102.6, 81.6, 73.5, 70.1, 60.9, 56.1, 56.0, 31.1, 6.8, 4.8. HRMS
(ESI): m/z [M + Na]+ calcd for C19H30O4SiNa+: 373.1806; found: 373.1802.
triethyl((1-(4-(trifluoromethyl)phenyl)but-3-yn-1-yl)oxy)silane (12e) Prepared according to general
1
procedure C from 11e (643 mg, 3 mmol) to give 853 mg colorless oil, 87%: H NMR (500 MHz,
CDCl3) (major rotamer) δ 7.54 – 7.50 (m, 2H), 7.44 – 7.41 (m, 2H), 4.79 (t, J = 6.4 Hz, 1H), 2.57 –
2.52 (m, 1H), 2.43 (ddd, J = 16.6, 6.6, 2.7 Hz, 1H), 1.90 (t, J = 2.7 Hz, 1H), 0.83 (t, J = 7.9 Hz, 9H),
0.53 – 0.47 (m, 6H); 13C NMR (126 MHz, CDCl3) δ 147.8, 129.6, 126.2, 126.1, 125.1 (q, J = 3.8 Hz),
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The Journal of Organic Chemistry
80.7, 71.6, 70.6, 30.8, 6.7, 4.7. HRMS (ESI): m/z [M + Na]+ calcd for C17H23F3OSiNa+: 351.1363;
found: 351.1361.
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triethyl((1-(4-fluorophenyl)but-3-yn-1-yl)oxy)silane (12f) Prepared according to general procedure
C from 11f (493 mg, 3 mmol) to give 649 mg colorless oil, 77%: 1H NMR (500 MHz, CDCl3) (major
rotamer) δ 7.34 (ddd, J = 8.3, 5.4, 2.3 Hz, 2H), 7.01 (td, J = 8.7, 2.3 Hz, 2H), 4.79 (td, J = 6.5, 2.3 Hz,
1H), 2.60 (ddt, J = 16.6, 6.1, 2.5 Hz, 1H), 2.47 (ddt, J = 16.6, 6.6, 2.5 Hz, 1H), 1.95 (q, J = 2.5 Hz,
1H), 0.89 (td, J = 7.9, 2.3 Hz, 9H), 0.55 (pd, J = 7.6, 2.1 Hz, 6H); δ 13C NMR (126 MHz, CDCl3) δ
162.5 (d, 245 Hz), 139.7, 127.5 (d, 8.0 Hz), 115.0 (d, 21.4 Hz), 81.2, 72.8, 70.2, 31.0, 6.7, 4.7. HRMS
(ESI): m/z [M + Na]+ calcd for C16H23FOSiNa+: 301.1394; found: 301.1406.
triethyl((1-(2-fluorophenyl)but-3-yn-1-yl)oxy)silane (12g)
Prepared according to general
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procedure C from 11g (493 mg, 3 mmol) to give 798 mg colorless oil, 95%: H NMR (500 MHz,
CDCl3) δ 7.47 (td, J = 7.4, 1.8 Hz, 1H), 7.20 – 7.13 (m, 1H), 7.07 (td, J = 7.6, 1.2 Hz, 1H), 6.92 (ddd,
J = 10.4, 8.2, 1.2 Hz, 1H), 5.14 (t, J = 6.1 Hz, 1H), 2.52 (dd, J = 6.1, 2.6 Hz, 2H), 1.86 (t, J = 2.6 Hz,
13
1H), 0.83 (t, J = 7.9 Hz, 9H), 0.60 – 0.45 (m, 6H); C NMR (126 MHz, CDCl3) δ 160.2 (d, 245 Hz),
130.9 (d, 13.5 Hz), 128.9 (d, 8.2 Hz), 127.8, 124.0, 114.8, 81.0, 69.9, 66.4, 29.6, 6.7, 4.6. HRMS
(ESI): m/z [M + Na]+ calcd for C16H23FOSiNa+: 301.1394; found: 301.1411.
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4-(1-((triethylsilyl)oxy)but-3-yn-1-yl)benzonitrile (12h) Prepared according to general procedure C
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from 11h (514 mg, 3 mmol) to give 780 mg colorless oil, 91%: H NMR (500 MHz, CDCl3)(major
rotamer) δ 7.58 – 7.53 (m, 2H), 7.44 – 7.41 (m, 2H), 4.78 (t, J = 6.4 Hz, 1H), 2.58 – 2.52 (m, 1H),
2.42 (ddd, J = 16.6, 6.9, 2.7 Hz, 1H), 1.90 (t, J = 2.7 Hz, 1H), 0.82 (t, J = 7.9 Hz, 9H), 0.54 – 0.47 (m,
6H); 13C NMR (126 MHz, CDCl3) δ 149.1, 132.0, 126.7, 118.9, 111.4, 80.3, 72.7, 70.9, 30.6, 6.7, 4.7.
HRMS (ESI): m/z [M + Na]+ calcd for C17H23NOSiNa+: 308.1441; found: 308.1449.
2-(1-((triethylsilyl)oxy)but-3-yn-1-yl)pyridine (12i) Prepared according to general procedure C from
11i (442 mg, 3 mmol) to give 760 mg colorless oil, 97%: 1H NMR (500 MHz, CDCl3) δ 8.54 – 8.43 (m,
1H), 7.82 (s, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.28 (d, J = 6.1 Hz, 1H), 5.10 (s, 1H), 2.72 (dd, J = 5.5, 2.7
Hz, 2H), 1.85 (d, J = 5.3 Hz, 1H), 0.88 (dt, J = 23.3, 8.0 Hz, 19H), 0.56 (ddt, J = 15.5, 13.0, 7.7 Hz,
6H); 13C NMR (126 MHz, CDCl3) δ 161.6, 146.2, 138.8, 123.1, 121.7, 80.1, 72.5, 70.7, 29.1, 6.8, 4.7.
HRMS (ESI): m/z [M + Na]+ calcd for C15H23NOSiNa+: 284.1441; found: 284.1467.
triethyl((1-(furan-3-yl)but-3-yn-1-yl)oxy)silane (12j) Prepared according to general procedure C
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from 11j (408 mg, 3 mmol) to give 721 mg colorless oil, 96%: H NMR (500 MHz, CDCl3) δ 7.45 –
7.36 (m, 2H), 6.46 (dd, J = 1.9, 0.9 Hz, 1H), 4.89 – 4.81 (m, 1H), 2.63 (ddd, J = 16.5, 6.1, 2.7 Hz, 1H),
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2.54 (ddd, J = 16.5, 6.9, 2.7 Hz, 1H), 2.01 (t, J = 2.7 Hz, 1H), 1.05 – 0.89 (m, 9H), 0.72 – 0.54 (m,
6H); 13C NMR (126 MHz, CDCl3) δ 142.9, 139.0, 128.6, 108.7, 81.2, 70.2, 66.4, 29.8, 6.8, 4.7. HRMS
(ESI): m/z [M + Na]+ calcd for C14H22O2SiNa+: 273.1281; found: 273.1299.
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(S)-triethyl((1-(furan-3-yl)but-3-yn-1-yl)oxy)silane [(S)12j] Prepared according to general
procedure C from (S)11j (528 mg, 3.9 mmol) to give 920 mg colorless oil, 95%: Spectra were
identical to that of racemic 12j. [a]D20 -9.59° (c. 0.99 , CHCl3).
triethyl((1-(thiophen-2-yl)but-3-yn-1-yl)oxy)silane (12k) Prepared according to general procedure
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C from 11k (457 mg, 3 mmol) to give 796 mg colorless oil, 99%: H NMR (500 MHz, CDCl3) δ 7.14
(dd, J = 5.0, 1.3 Hz, 1H), 6.96 – 6.84 (m, 2H), 5.02 (td, J = 6.5, 0.8 Hz, 1H), 2.63 (ddd, J = 16.6, 6.4,
2.6 Hz, 1H), 2.54 (ddd, J = 16.6, 6.6, 2.7 Hz, 1H), 0.85 (t, J = 7.9 Hz, 9H), 0.53 (qd, J = 7.9, 3.2 Hz,
6H); 13C NMR (126 MHz, CDCl3) δ 148.3, 126.3, 124.2, 123.4, 81.0, 70.5, 69.8, 31.4, 6.8, 4.7. HRMS
(ESI): m/z [M + Na]+ calcd for C14H22SOSiNa+: 289.1053; found: 289.1031.
((1-cyclohexylbut-3-yn-1-yl)oxy)triethylsilane (12l) Prepared according to general procedure C
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from 11l (457 mg, 3 mmol) to give 750 mg colorless oil, 93%: H NMR (500 MHz, CDCl3) δ 3.55 –
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3.48 (m, 1H), 2.35 – 2.20 (m, 2H), 1.90 (t, J = 2.7 Hz, 1H), 1.69 (dddt, J = 14.5, 12.7, 3.3, 1.8 Hz, 2H),
1.59 (dqd, J = 13.5, 3.3, 1.6 Hz, 2H), 1.52 – 1.44 (m, 2H), 1.24 – 1.06 (m, 3H), 1.09 – 0.92 (m, 2H),
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0.90 (t, J = 7.9 Hz, 9H), 0.61 – 0.47 (m, 6H); C NMR (126 MHz, CDCl3) δ 82.1, 74.9, 69.7, 42.5,
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29.4, 27.4, 26.6, 26.4, 26.2, 24.7, 6.9, 5.1. HRMS (ESI): m/z [M + Na]+ calcd for C16H30OSiNa+:
289.1958; found: 289.1970.
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triethyl(pent-4-yn-2-yloxy)silane (12m) Prepared according to general procedure C from
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commercially available 4-pentyn-2-ol, (252 mg, 3 mmol) to give 584 mg colorless oil, 97%: H NMR
(500 MHz, CDCl3) δ 0.61 (q, J = 7.9 Hz, 6H), 0.96 (t, J = 7.9 Hz, 9H), 1.26 (d, J = 6.1 Hz, 3H), 1.99
(t, J = 2.7 Hz, 1H), 2.26 (ddd, J = 16.5, 7.4, 2.7 Hz, 1H), 2.37 (ddd, J = 16.5, 5.2, 2.7 Hz, 1H), 3.88 –
4.01 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 81.8, 69.8, 67.3, 29.4, 23.3, 6.8, 4.8. HRMS (ESI): m/z
[M + Na]+ calcd for C11H22OSiNa+: 221.1332; found: 221.1327.
(R)-triethyl(pent-4-yn-2-yloxy)silane [(R)12m] Prepared according to general procedure C from
crude (R)11m (188 mmol), imidazole (19 g, 282 mmol), DMAP (2.3 g, 18.8 mmol), and
chlorotriethylsilane (31.7 mL, 188 mmol) in CH2Cl2 to give 25.1 g clear oil, 67% over two steps.
Spectra were identical to that of racemic 12m. [a]D20 +5.15° (c. 0.97 , CHCl3).
((2,2-dimethylhex-5-yn-3-yl)oxy)triethylsilane (12n) Prepared according to general procedure C
from 11n (378 mg, 3 mmol) to give 713 mg colorless oil, 99%: 1H NMR (500 MHz, CDCl3) δ 3.52 (dd,
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J = 7.0, 4.0 Hz, 1H), 2.44 (ddd, J = 17.1, 4.0, 2.7 Hz, 1H), 2.17 (ddd, J = 17.0, 7.0, 2.7 Hz, 1H), 1.97
(t, J = 2.7 Hz, 1H), 0.98 (t, J = 8.0 Hz, 8H), 0.88 (s, 9H), 0.67 (qd, J = 7.9, 1.9 Hz, 6H); 13C NMR (126
MHz, CDCl3) δ 83.9, 79.5, 69.6, 36.0, 25.9, 23.5, 7.1, 5.4. HRMS (ESI): m/z [M + Na]+ calcd for
C14H28OSiNa+: 263.1802; found: 263.1795.
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(dec-1-yn-4-yloxy)triethylsilane (12o) Prepared according to general procedure C from 11o (417
mg, 3.00 mmol) to give 722 mg colorless oil, 95%: 1H NMR (500 MHz, CDCl3) δ 3.77 – 3.69 (m, 1H),
2.30 – 2.22 (m, 2H), 1.91 (t, J = 2.7 Hz, 1H), 1.59 – 1.42 (m, 4H), 1.27 – 1.19 (m, 5H), 0.90 (td, J =
8.0, 3.4 Hz, 10H), 0.85 – 0.80 (m, 3H), 0.59 – 0.51 (m, 6H); 13C NMR (126 MHz, CDCl3) δ 81.8, 70.9,
69.8, 36.7, 31.9, 27.5, 24.9, 22.7, 14.1, 6.9, 4.9. HRMS (ESI): m/z [M + Na]+ calcd for C16H32OSiNa+:
291.2115; found: 291.2137.
(E)-4-iodo-1-phenylbut-3-en-1-ol (6a) Prepared according to general procedure A from 12a, purified
by column chromatography (10% - 20% EtOAc/hexane) to give 504 mg light yellow, viscous oil, 92%:
Rf = 0.49 [silica gel, 20% EtOAc in pentanes] deep blue with vanillin stain; 1H NMR (500 MHz, CDCl3
δ 7.43 – 7.25 (m, 5H), 6.54 (dt, J = 14.7, 7.4 Hz, 1H), 6.16 (dt, J = 14.4, 1.3 Hz, 1H), 4.76 (dd, J = 7.5,
5.3 Hz, 1H), 2.57 – 2.43 (m, 2H), 1.95 (br. s, 1H); 13C NMR (126 MHz, CDCl3) δ 143.3, 142.1, 128.6,
127.9, 125.7, 77.9, 73.0, 45.5. HRMS (ESI): m/z [M + H – H2O]+ calcd for C10H10I+: 256.9821; found:
256.9824.
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(S,E)-4-iodo-1-phenylbut-3-en-1-ol [(S)6a] Prepared according to general procedure A (reagents
scaled linearly) from (S)12a (2.60 g, 10 mmol) to give 2.42 g clear oil, 88%: Spectra were identical to
that of racemic 6a. [a]D20 -30.36° (c. 1.43, CHCl3).
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(E)-4-iodo-1-(3-methoxyphenyl)but-3-en-1-ol (6b) Prepared according to general procedure A from
12b, purified by column chromatography (10% - 20% EtOAc/hexane) to give 509 mg light yellow,
viscous oil, 83%: Rf = 0.39 [silica gel, 20% EtOAc in pentanes] deep blue with vanillin stain; 1H NMR
(500 MHz, CDCl3) δ 7.30 – 7.26 (m, 1H), 6.95 – 6.86 (m, 2H), 6.87 – 6.80 (m, 1H), 6.54 (dt, J = 14.7,
7.5 Hz, 1H), 6.15 (dt, J = 14.4, 1.3 Hz, 1H), 4.79 – 4.68 (m, 1H), 3.82 (s, 3H), 2.53 – 2.45 (m, 2H),
2.03 – 1.95 (br s, 1H); 13C NMR (126 MHz, CDCl3) δ 159.8, 145.0, 142.1, 129.6, 118.0, 113.3, 111.2,
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77.9, 72.9, 55.3, 45.4. HRMS (ESI): m/z [M + HCOO]- calcd for C12H14IO4 : 348.9942; found: 348
.9970.
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(S,E)-4-iodo-1-(3-methoxyphenyl)but-3-en-1-ol [(S)6b] Prepared according to general procedure A
(reagents scaled linearly) from (S)12b (1.16 g, 4.0 mmol) to give 1.13 g clear oil, 93%: Spectra were
identical to that of racemic 6b. [a]D20 -20.85° (c. 0.83, CHCl3).
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(E)-4-iodo-1-(4-methoxyphenyl)but-3-en-1-ol (6c) Prepared according to general procedure A from
12c, purified by column chromatography (10% - 20% EtOAc/hexane) to give 596 mg light yellow,
viscous oil, 98%: Rf = 0.44 [silica gel, 20% EtOAc in pentanes] deep blue with vanillin stain; 1H NMR
(500 MHz, CDCl3) δ 7.28 – 7.24 (m, 2H), 6.95 – 6.86 (m, 2H), 6.53 (dt, J = 14.6, 7.7, 1H), 6.14 (dt, J
= 14.4, 1.3 Hz, 1H), 4.70 (ddd, J = 8.1, 5.2, 3.1 Hz, 1H), 3.81 (s, 3H), 2.66 – 2.38 (m, 2H), 1.88 (d, J =
3.2 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 159.2, 142.3, 135.4, 127.0, 113.9, 77.8, 72.6, 55.3, 45.45.
+
HRMS (ESI): m/z [M + Na]+ calcd for C11H13INaO2 : 326.9852; found: 326.9831.
(E)-4-iodo-1-(3,4,5-trimethoxyphenyl)but-3-en-1-ol (6d) Prepared according to general procedure
A from 12d, purified by column chromatography (20% - 40% EtOAc/hexane) to give 692 mg light
yellow, viscous oil, 95%: Rf = 0.16 [silica gel, 30% EtOAc in pentanes] deep blue with vanillin stain; 1H
NMR (500 MHz, CDCl3) δ 6.58 – 6.42 (m, 3H), 6.09 (dt, J = 14.4, 1.3 Hz, 1H), 4.62 (dd, J = 7.3, 5.3
Hz, 1H), 3.80 (s, 6H), 3.77 (s, 3H), 2.50 – 2.28 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 153.3, 142.1,
139.1, 118.6, 102.5, 78.0, 73.2, 60.9, 56.2, 45.5. HRMS (ESI): m/z [M + Na]+ calcd for C13H17IO4Na+:
387.0064; found: 387.0064.
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