Deoxygenation of Unhindered Alcohols via Reductive Dealkylation of Derived Phosphate Esters

Article abstract of DOI:10.1021/acs.joc.6b01699

Primary alcohols can be deoxygenated cleanly and in yields of 60-95% by reduction of derived diphenyl phosphate esters with lithium triethylborohydride in tetrahydrofuran at room temperature. Selective deoxygenation of a primary alcohol in the presence of a secondary alcohol was demonstrated. The two-step process can be performed in one pot, making it simple and convenient.

Full text of DOI:10.1021/acs.joc.6b01699

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Note
Deoxygenation of Unhindered Alcohols via
Reductive Dealkylation of Derived Phosphate Esters
Sarwat Chowdhury, and Robert F. Standaert
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01699 • Publication Date (Web): 15 Sep 2016
Downloaded from http://pubs.acs.org on September 16, 2016
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Deoxygenation of Unhindered Alcohols via Reductive Dealkylation of Derived Phosphate
Esters
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†,‡
,§,
ꢀ
Sarwat Chowdhury and Robert F. Standaert*
†
The University of Illinois at Chicago, Department of Chemistry, 845 West Taylor Street,
‡
Chicago, IL 60304, U.S.A. Current address: Fred Hutchinson Cancer Research Center, 1100
Fairview Ave. N., Seattle, WA 98109, U.S.A.
§
Oak Ridge National Laboratory, Biosciences Division, PO Box 2008, Oak Ridge, TN 37831ꢀ
6445, U.S.A.
ꢀ
University of Tennessee, Department of Biochemistry and Cellular & Molecular Biology,
Knoxville, TN 37996, U.S.A.
standaertrf@ornl.gov
Notice of Copyright
This manuscript has been authored by UTꢀBattelle, LLC under Contract No. DEꢀAC05ꢀ
0
0OR22725 with the U.S. Department of Energy. The United States Government retains and the
publisher, by accepting the article for publication, acknowledges that the United States
Government retains a nonꢀexclusive, paidꢀup, irrevocable, worldꢀwide license to publish or
reproduce the published form of this manuscript, or allow others to do so, for United States
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Government purposes. The Department of Energy will provide public access to these results of
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(http://energy.gov/downloads/doeꢀpublicꢀaccessꢀplan).
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×
O
P
H
BEt3
(
PhO) P(O)Cl
2
HO
R
O
O
R
H
R
(Li+)
O
Abstract: Primary alcohols can be deoxygenated cleanly and in yields of 60ꢀ95% by reduction
of derived diphenyl phosphate esters with lithium triethylborohydride in tetrahydrofuran at room
temperature. Selective deoxygenation of a primary alcohol in the presence of a secondary alcohol
was demonstrated. The twoꢀstep process can be performed in one pot, making it simple and
convenient.
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1
–4
Deoxygenation of alcohols is a common and valuable synthetic procedure. The most widely
used methods for accomplishing this transformation fall into two categories, radical and
nucleophilic, with largely complementary applications. Radical deoxygenations are typified by
5
the BartonꢀMcCombie reaction, which involves freeꢀradical chain reduction of a thiocarbonyl
derivative of the alcohol. The process is mild, efficient and compatible with a wide array of
functional groups. As such, it has found many applications, and numerous modifications of the
1
–4,3–9
basic approach have been reported over the years.
It is most suited to secondary alcohols
1
0,11
12–14
but has also found application to tertiary
and primary
alcohols. The latter typically
require elevated temperatures, and clever alternatives have been introduced in which the
intermediate primary radical is generated at ambient or lower temperature through
1
5
decomposition of monoalkyl diazenes, or more recently, by photochemical reduction of alkyl
1
6
17
18
bromides, iodides or 3,5ꢀbis(trifluoromethyl)benzoates using precious metal catalysts.
Nucleophilic deoxygenations typically employ a firstꢀ or secondꢀrow metal hydride
reagent, such as lithium aluminum hydride or lithium triethylborohydride, to reduce an activated
1
9ꢀ21
derivative of the alcohol (halide or sulfonate ester).
These reactions are complementary to
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radical methods in that they are most efficient for unhindered primary alcohols, and their main
limitation is incompatibility with reducible functional groups. Hydrosilanes, in combination with
Brønsted or Lewis acids, have proven to be effective nucleophiles for the deoxygenation of
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alcohols.
Hydrosilane reductions typically proceed through the S 1 mechanism and are
N
hence effective only for tertiary, secondary or benzylic alcohols. The introduction of
tris(pentafluorophenyl)borane as a catalyst extended the scope of the reaction to primary alcohols
2
5,26
and ethers, which are presumed to react by an S 2ꢀlike mechanism,
and a copper catalyst has
N
proven effective for reduction of triflates and iodides derived from primary or secondary
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alcohols.
Scheme 1. Deoxygenation of alcohols via reduction of derived phosphate esters
O
(
R'O) P(O)Cl
H BEt3
2
(
R'O) P
2
HO
R
O
R
H
R
Our exploration of a new method ensued from our fortuitous discovery that lithium
trialkylborohydrides (triethyl or triꢀsꢀbutyl) rapidly dealkylate phosphonic diesters through
reduction at carbon via a presumed S 2 mechanism, with no indication of reaction at
N
28
phosphorus. Exclusively monoꢀdealkylated products were obtained, and over reduction was not
observed even after addition of excess hydride reagent and prolonged stirring. This observation
immediately suggests the possibility of using phosphonates as intermediates for the
deoxygenation of alcohols, and we expected that phosphate esters might prove more reactive due
to the weaker basicity of the leaving group (Scheme 1). For this study we chose the triethyl
2
0
reagent because of its less hindered steric environment and exceptional nucleophilicity.
Phosphate triesters are easily obtained through derivatization of alcohols. Implementation
of our scheme required that the groups introduced through phosphorylation be refractory to SN2
sustitution, such that regioselective dealkylation could be effected at the desired site. Two
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candidates were initially considered, diphenyl phosphates (1) and pinacol phosphates (2) (Figure
1). Of these, the former were judged preferable due to their stability and ease of synthesis from
inexpensive, readily available diphenyl chlorophosphate (3).
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O
P
O
P
O
O
P
R
R
O
O
O
O
O
Cl
O
O
1
2
3
Figure 1. Phosphate esters amenable for deoxygenation (1 and 2) and an inexpensive
phosphorylating reagent (3).
Phosphorus derivatives have been used to activate alcohols for subsequent deoxygenation
by radical and singleꢀelectron transfer processes. For example, phosphites can undergo Bartonꢀ
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McCombie deoxygenation and diphenyl phosphinates can be electrochemically deoxygenated
3
0
through an analogous pathway. Phosphate esters and related species have been used to activate
3
1–34
phenols, enols and alcohols for subsequent reduction using alkalai metals.
Less work has
been done in the area of nucleophilic processes. Diethyl alkylphosphonates can be deethylated by
3
5
Et SiH in conjunction with B(C F ) as catalyst, presumably with liberation of ethane, and this
3
6 5 3
reaction could potentially be applied for deoxygenation in analogy to the approach described
+
–
herein. Hendrickson employed a phosphonium anhydride reagent, (Ph P ) O•2(CF SO ), to
3
2
3
3
convert alcohols into highly reactive triphenylphosphonium derivatives that could be reduced in
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situ with sodium borohydride. Earlier, Haley et al. had activated neryl and geranyl alcohols as
their diphenylphosphate esters and found that these substrates could be reduced to the
corresponding alkadienes with sodium borohydride in a hot mixture of aqueous sodium
hydroxide and diglyme. The main products were consistent with S 2 substitution, but small
N
amounts of allylically rearranged and cyclized hydrocarbons formed, likely the result of
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carbocation formation in the reaction medium. This promising observation was not further
explored as a general approach to deoxygenation.
We found that the phosphorylation–reduction sequence using LiBHEt proceeds
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smoothly at room temperature in THF, can be effected in one pot, gives high yields of
deoxygenated primary alcohols, and can selectively dealkylate primary over secondary alcohols.
As such, the diphenyl phosphate derivative provides a convenient general alternative to halides
and sulfonate esters for nucleophilic deoxygenation.
Our first model substrate was 6ꢀphenylhexanol (4). Treatment of this alcohol with
diphenyl chlorophosphate and DMAP in dichloromethane generated the desired phosphotriester,
which after isolation was treated with 1.7 equiv of LiBHEt in THF. To our gratification, the
3
reduction proceeded to completion within five hours at room temperature, affording
hexylbenzene in 82% isolated yield over two steps (based on alcohol 4). Given this initial
success, we undertook a broader study of the reaction’s scope and sought to streamline the
experimental procedures. Our study included a set of primary alcohols (Table 1) with different
steric and chemical environments, secondary alcohols, and a steroidal diol containing both
primary and secondary hydroxyl groups.
We first examined compatibility of the process with primary amides and urethanes. The
NꢀBoc and Nꢀ2,4ꢀdimethoxybenzoyl derivatives of 6ꢀaminohexanꢀ1ꢀol (6 and 8, respectively)
were deoxygenated cleanly. In these cases, >2 equiv. of hydride were required to cause complete
reduction due to an acid–base reaction with the amide. The rapid deprotonation of primary
amides by LiHBEt is wellꢀknown, as is the consequent sluggishness of nucleophilic attack at the
3
3
8
amide carbonyl. Although the amidate ion could hypothetically initiate side reactions, such as
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nucleophilic attack at phosphorus or carbon (e.g, cyclization of 10 to NꢀBocꢀpiperidine), no
evidence of such processes was observed.
Table 1. Deoxygenation of representative primary alcohols
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Method A: CH Cl , DMAP, 3, rt
O
P
OPh
LiEt BH
2
2
3
R–OH
R–H
OPh
RO
Method B: CH Cl , cat. DMAP,
THF, rt
2
2
Et N, 3, rt
3
Yield
Substrate Product
Entry
Method
(X=OH)
(X=H)
Phosphorylation Reduction Overall
X
4
5
B
A
82
O
X
b
N
6
7
9
86
95
~100
~100
86
H
MeO
OMe
O
b
X
8
A
95
72
t-BuO
N
H
O
10
11
13
B
B
t-BuO
N
X
H
O
X
59
1
1
2
4
a
(64)
X
15
A
87
70
61
O
BnO
BnO
OMe
OBn
a
based on recovered substrate
Having successfully employed the deoxygenation protocol on several unhindered primary
alcohols, we next examined reduction of a model allylic alcohol, the monobenzyl ether of cisꢀ
3
9
buteneꢀ1,4ꢀdiol, to assess whether S 2’ substitution was competitive with S 2. Application of
N
N
the phosphorylation–reduction protocol to this substrate afforded the S 2 product 13. Though the
N
yield was modest (59%; 64% based on recovered starting 12), no evidence of S 2’ reduction or
N
elimination products was detected.
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A βꢀbranched alcohol, glucopyranoside 14, was next examined to test the applicability of
this method on a sterically crowded primary alcohol. The substrate 14 was first converted to
corresponding phosphate, and the resultant phosphate was treated with LiHBEt at room
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temperature. Gratifyingly, the desired 6ꢀdeoxy sugar 15 was obtained in 70% yield. This
example illustrates that reaction is effective with sterically hindered primary alcohols and
provides access to 6ꢀdeoxy sugars.
We proceeded to investigate the effectiveness of the procedure on secondary alcohols. 2ꢀ
Octanol was converted in high yield to the corresponding diphenylphosphate. Reaction of this
compound with LiHBEt for 4 h at room temperature produced nꢀoctane as the major product,
3
but conversion was poor (44% by GC using nꢀdecane as an internal standard, Scheme 2).
Scheme 2. Deoxygenation of 2-octanol.
OH
n-C H
3, DMAP, CH Cl
OP(O)(OPh)2
n-C H
2
2
6
13
rt, 2h, 89%
6
13
LiEt BH, THF
3
n-C H
6
13
rt, 4h, 44%
Two cyclic secondary alcohols, exoꢀnorborneol and (1S,2R,5S)ꢀmenthol, were likewise
converted to diphenyl phosphate derivatives. After treatment with LiHBEt in THF, no
3
deoxygenated products could be detected, and unreacted starting materials were recovered. A
third secondary alcohol, diacetone glucose (1,2:5,6ꢀdiꢀOꢀisopropylideneꢀαꢀDꢀglucofuranose),
was likewise readily phosphorylated with 3 but produced an intractable mixture upon reduction.
We subsequently attempted to make the pinacol phosphate of diacetone glucose using either
pinacolyl chlorophosphate or pinacolyl chlorophosphite. However, the products proved too
40
unstable to isolate and purify, consistent with the known lability of pinacol phosphates. Thus,
deoxygenation of secondary alcohols via derived diphenyl phosphates may proceed with limited
success for unhindered substrates, but is likely to fail completely for hindered ones.
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Having found as expected that the reduction is sluggish with hindered secondary systems,
we sought to determine whether it was possible to deoxygenate a primary alcohol selectively in
the presence of a secondary alcohol. We chose lithocholanyl alcohol 19, formed by reduction of
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lithocholic acid with LiAlH , as a test substrate. Compound 19 was first bisphosphorylated with
4
diphenyl chlorophosphate, and after isolation, the crude bisꢀphosphate was subjected to treatment
with LiHBEt . In accordance with expectation, only the primary phosphate was reduced under
3
the reaction conditions. The secondary phosphate remained intact, affording
monophosphorylated compound 20 as the only product (Scheme 3).
a
Scheme 3. Selective reduction of a primary phosphate ester.
Me
Me
Me
Me
OH
H
H
H
2 steps
Me
H
Me
H
61%
H
H
H
H
HO
(PhO) P(O)O
2
H
H
19
20
a
Conditions: 1) 3, DMAP, CH Cl , rt, 3h; 2) LiHBEt , THF, rt, 4.5 h.
2
2
3
In order to simplify the twoꢀstep phosphorylation–deoxygenation process, we explored
development a oneꢀpot protocol (Scheme 4). Success was realized with a switch to THF as
solvent with nꢀBuLi as base for the phosphorylation reaction. Thus, a solution of diol 19 in THF
was treated with 2.1 equiv. of nꢀBuLi, followed by 2.1 equiv. of diphenylphosphoryl chloride to
effect bisꢀphosphorylation. After 2 hours, LiHBEt (1.3 equiv.) was added, and the reaction was
3
stirred at room temperature for 14 h to effect selective reduction of the primary phosphate. The
crude product was treated with sodium bis(2ꢀmethoxyethoxy)aluminum hydride (1.2 equiv) to
cleave the secondary phosphate group, liberating the secondary alcohol 21 in 82% overall yield
for the three steps. This last sequence of reactions (21→22) illustrates the clear dichotomy
between boron hydrides, which reduce carbon (19→20), and aluminum hydrides, which reduce
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phosphorus (20→21). It further illustrates how the phosphate ester can be used as a protecting
group for alcohols.
Scheme 4. Selective deoxygenation of a primary alcohol employing one-pot
phosphorylation–reduction procedure.
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Me
Me
Me
Me
Me
Me
OH
H
H
H
H
H
1
) n-BuLi, THF, rt
then 3, THF, rt, 2 h
Me
H
Me
H
NaAlH (OCH CH OCH )
2
2
2
3 2
Me
H
H
H
2) LiEt BH, THF, rt, 14 h
3
H
H
toluene, 0 °C → rt, 14 h
H
H
2
1
HO
(PhO) P(O)O
2
HO
82% overall
H
H
H
One Pot
1
9
20
Conclusions
Primary alcohols can be deoxygenated cleanly and in highꢀyield by reduction of their diphenyl
phosphate esters with LiBHEt in THF at room temperature. The twoꢀstep procedure can be
3
effected in a oneꢀpot process that is environmentally friendly in that no halogenated solvents are
required for the reaction or workup, and in that no heating or cooling is required. The process
works less well with simple secondary alcohols and fails with hindered ones. Selective
deoxygenation of a primary alcohol in the presence of a secondary one was readily effected.
Overall, diphenyl phosphate esters are a readily accessible and useful alternative to sulfonate
esters and halides for deoxygenation of primary alcohols.
Experimental Section
General Methods. All reactions were run in glassware sealed with rubber septa and stirred
magnetically under nitrogen unless otherwise specified. Tetrahydrofuran (THF) and methylene
chloride (DCM) were dried by use of a sorbentꢀbased purification system. Other commercial
reagents and solvents were used without purification. Flash chromatography was performed
using silica gel 60 (40ꢀ63 µm particle size), and TLC was performed on silica gel 60 F254 plates
(glassꢀbacked, 0.25 mm layer thickness). TLC chromatograms were visualized with iodine vapor
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4
5
6
7
8
9
or KMnO . NMR spectra were recorded at the indicated frequencies and were calibrated using
4
internal tetramethylsilane or solvent peaks (CHCl = δ 7.27, CDCl = δ 77.23). Highꢀresolution
3
3
mass spectra were obtained using electrospray ionization (ESI) with either a quadrupole–timeꢀofꢀ
flight (QTOF) or a Fourier transform ion cyclotron resonance (FTICR) mass spectrometer.
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1
ꢀPhenylhexane (5). To a stirred solution of 6ꢀphenylhexanꢀ1ꢀol (4, 0.1095 g, 0.6142 mmol) and
DMAP (22 mol%, 0.1359 mmol, 0.1665 g) in 4 mL of THF under nitrogen was added
triethylamine (1.2 equiv, 0.5609 mmol, 0.08 mL) followed by diphenyl phosphoryl chloride (1.2
equiv, 0.7370 mmol, 0.15 mL) at room temperature. After completion of the reaction (3 h), the
reaction mixture was concentrated. The residue was taken up in ethyl acetate and washed with
water, 1N NaHCO and brine. The organic layer was dried with Na SO and concentrated in
3
2
4
vacuo to give phosphoric acid (6ꢀphenyl hexyl) diphenyl ester. The crude product was dissolved
in THF (4 mL) and LiHBEt (1.0 M in THF; 1.7 equiv, 1.0441 mmol, 1.0 mL). The reaction was
3
monitored by TLC, and upon consumption of the starting material, the reaction was quenched
with water and extracted with EtOAc (5×). The combined organic layer was dried with Na SO ,
2
4
and the solvent was evaporated under reduced pressure to afford the crude product. Purification
by flash chromatography using hexanes:ethyl acetate (6:1) afforded 0.0819 g (0.505 mmol, 82%)
1
of the product: R 0.89 (hexanes:EtOAc 1:1); H NMR (400 MHz, CDCl , δ) 7.22–7.19 (m, 2H),
f
3
7
.12–7.08 (m, 3H), 2.53 (t, J = 7.8 Hz, 2H), 1.57–1.48 (m, 2H), 1.35–1.20 (m, 6H), 0.81 (t, J =
1
3
6.8 Hz, 3H); C NMR (100 MHz, CDCl , δ) 143.2, 128.6, 128.4, 125.7, 36.2, 31.9, 31.7, 29.9,
3
2
9.2, 22.8, 14.3. NMR data are consistent with those reported in the Spectral Database for
4
1
Organic Compounds (SDBS).
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O
OH
N
H
MeO
OMe
Nꢀ(6ꢀhydroxyhexyl)ꢀ2,4ꢀdimethoxybenzamide (6). To a stirred solution of 6ꢀaminohexanol
0.1168 g, 0.9969 mmol) and triethylamine (1.0 equiv, 0.14 mL) in DCM (4 mL) was added
0
1
2
3
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0
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0
(
dropwise over 1 h a solution of 2,4ꢀdimethoxybenzoyl chloride (1.0 equiv, 0.2 g, 0.9969 mmol)
in 2 mL of DCM at 0 °C under nitrogen. After 3h, the reaction was quenched with water, and the
organic layer was evaporated off. The aqueous layer was extracted with ethyl acetate (3×), and
the combined organic layer was then dried with anhydrous Na SO and filtered. Evaporation of
2
4
the solvent afforded the crude product, which upon purification by flash chromatography using
DCM:methanol (93:7) as eluent afforded 0.2366 g (0.8409 mmol, 84%) of the product as white
1
solid: R 0.43 (DCM:methanol 95:5); H NMR (500 MHz, CDCl , δ) 8.15 (d, J = 8.7 Hz, 1H),
f
3
7
.77 (br t, J ≈ 6 Hz, 1H), 6.58 (dd, J = 8.8, 2.3 Hz, 1H), 6.46 (d, J = 2.3 Hz, 1H), 3.92 (s, 3H),
3.83 (s, 3H), 3.62 (t, J = 6.5 Hz, 2H), 3.43 (q, J = 5.8 Hz, 2H), 2.13 (br s, 1H), 1.64–1.52 (4H, m),
13
1
.46–1.35 (4H, m); C NMR (125 MHz, CDCl , δ) 165.3, 163.4, 158.9, 134.0, 114.8, 105.4,
3
98.7, 62.7, 56.1, 55.7, 39.5, 32.8, 29.8, 26.8, 25.4; HRMS (ESI–QTOF) calcd for C H NO Na
1
5
23
4
[
M+Na] 304.1525, found 304.1523.
O
OP(O)(OPh)2
N
H
MeO
OMe
Phosphoric acid, 6ꢀ(2,4ꢀdimethoxybenzamido)hexyl diphenyl ester (diphenyl phosphate of 6). To
a stirred solution of Nꢀ(6ꢀhydroxyhexyl)ꢀ2,4ꢀdimethoxybenzamide (6, 0.1196 g, 0.4251 mmol)
and DMAP (2.0 equiv, 0.1039 g, 0.8502 mmol) in DCM (7.5 mL) was added
diphenylphosphoryl chloride (2.0 equiv, 0.8502 mmol, 0.18 ml), and the reaction mixture was
stirred under nitrogen at room temperature. After 2 h, the solvent was evaporated. Ethyl acetate
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and water were added, and the organic layer was separated. The aqueous layer was washed with
ethyl acetate (2×), and the combined organic layer was washed with water, saturated NaHCO3
and brine, then dried with Na SO and concentrated under reduced pressure. Purification of the
2
4
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crude product by flash chromatography (DCM:methanol, 9:1) afforded 0.1878 g (86%) of the
product as colorless oil: IR (neat) 3412, 3070, 2937, 2857, 1652, 1605, 1533, 1489, 1463, 1284,
–1
1
1
264, 1209, 1190, 1165, 1010, 951, 768 cm ; H NMR (400 MHz, CDCl , δ) 8.18 (d, J = 8.8 Hz,
3
1H), 7.75 (br t, J ≈ 6 Hz, 1H), 7.35 (t, J = 8.3 Hz, 4H), 7.23–7.16 (m, 6H), 6.59 (dd, J = 6.5, 2.3
Hz, 1H), 6.47 (d, J = 2.3 Hz, 1H), 4.25 (q, J = 7.4 Hz, 2H), 3.91 (s, 3H), 3.83 (s, 3H), 3.41 (q, J =
1
3
5
.9 Hz, 2H), 1.72 (p, J = 6.8 Hz, 2H), 1.57 (p, J = 6.9 Hz, 2H), 1.41–1.23 (m, 4H); C NMR
(
100 MHz, CDCl , δ) 165.2, 163.3, 158.8, 150.7 (d, J = 6.8 Hz), 134.0, 129.9, 125.4 (d, J = 5.2
3
Hz), 120.2 (d, J = 5 Hz), 114.8, 105.3, 98.7, 69.4 (d, J = 6.5 Hz), 56.0, 55.6, 39.6, 30.2 (d, J =
6.7 Hz) 29.7, 26.6, 25.2; HRMS (ESI–QTOF) calcd for C H NO PNa [M+Na] 536.1814,
2
7
32
7
found 536.1828.
O
N
H
MeO
OMe
Nꢀhexylꢀ2,4ꢀdimethoxybenzamide (7). To a stirred solution of phosphoric acid 6ꢀ(2,4ꢀ
dimethoxybenzamido)hexyl diphenyl ester (diphenyl phosphate of 6) (0.0951 g, 0.1852 mmol) in
THF (1.3 mL) was added LiEt BH (1.0 M solution in THF; 1.3 equiv, 0.2410 mmol, 0.24 mL) at
3
room under nitrogen. After 1 h, TLC showed a trace of the starting material. Another 0.24 mL of
LiEt BH solution was added, and the reaction was stirred at room temperature. After 1.5 h the
3
reaction was judged complete by TLC, and it was quenched by addition of water. The mixture
was acidified so that the aqueous layer was at pH 1 and extracted with EtOAc (3×). The
combined EtOAc layer was dried with Na SO and evaporated under reduced pressure.
2
4
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Purification of the residue by flash chromatography (DCM:MeOH, 9:1) afforded 0.0491 g
(~100%) of the product as colorless oil: IR (neat) 3413, 2953, 2928, 2855, 1727, 1650, 1606,
–
1 1
1
536, 1498, 1438, 1309, 1264, 1209, 1169, 1104, 835 cm ; H NMR (400 MHz, CDCl , δ) 8.20
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0
1
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0
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(d, J = 8.7 Hz, 1H), 7.76 (br s, 1H), 6.59 (dd, J = 8.8, 2.3 Hz, 1H), 6.48 (d, J = 2.3 Hz, 1H), 3.93
(s, 3H), 3.84 (s, 3H), 3.44 (td, J = 5.6, 1.3 Hz, 2H), 1.60 (p, J = 7.3 Hz, 2H), 1.44–1.28 (m, 6H),
13
0
.90 (t, J = 6.9 Hz, 3H); C NMR (100 MHz, CDCl , δ) 165.2, 163.3, 158.9, 134.0, 114.9, 105.3,
3
98.7, 56.0, 55.7, 39.8, 31.7, 29.8, 27.0, 22.8, 14.2.
O
OP(O)(OPh)2
t-BuO
N
H
Phosphoric acid 6ꢀ(tertꢀbutoxycarboxamido)hexyl diphenyl ester (diphenyl phosphate of 8). To a
stirred solution of 6ꢀ(tertꢀbutoxycarboxamido)hexanol (8, 0.3805 g, 1.7509 mmol) and DMAP
(
2.0 equiv, 3.5018 mmol, 0.4277 g) in DCM (30 mL) was added diphenyl phosphoryl chloride
2.0 equiv, 3.5018 mmol, 0.73 mL) at room temperature under nitrogen. The reaction went to
(
completion within 1h, after which it was concentrated and the residue was taken up in ethyl
acetate (40 mL) and water (15 mL). The ethyl acetate layer was separated, and the aqueous layer
was extracted with ethyl acetate (15mL). The combined ethyl acetate layer was washed
sequentially with water, 1N NaHCO and brine, then dried with Na SO and evaporated to
3
2
4
dryness to afford the target compound as a white solid (0.7507 g, 1.6701 mmol, 95%): R 0.2
f
1
hexanes:EtOAc 2:1); H NMR (400 MHz, CDCl , δ) 7.37–7.28 (m, 4H), 7.24–7.11 (m, 6H), 4.63
3
(br s, 1H), 4.22 (q, J = 6.6 Hz, 2H), 3.05 (br q, J = 6.3 Hz, 2H), 1.67 (p, J = 6.9 Hz, 2H), 1.43 (s,
1
3
9
7
3
4
H) 1.48–1.36 (m, 2H), 1.36–1.18 (m, 4H); C NMR (100 MHz, CDCl , δ ) 156.1, 150.6 (d, J =
3
.3 Hz), 129.8, 125.4, 120.1 (d, J = 4.8 Hz), 79.0, 69.3 (d, J = 6.7 Hz), 40.4, 30.1 (d, J = 6.7 Hz),
+
0.0, 28.5, 26.2, 25.1; HRMS (ESI–FTICR) calcd for C H NO P [M+H] 450.20455, found
2
3
33
6
50.20352.
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O
t-BuO
N
H
6
ꢀ(tertꢀButoxycarboxamido)hexane (9). A solution of phosphoric acid 6ꢀ(tertꢀ
butoxycarboxamido)hexyl diphenyl ester (diphenylphosphate of 8) (0.0540 g, 0.1201 mmol) in
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THF (0.8 mL) was treated with LiHBEt (1.0 M solution in THF; 1.2 equiv, 0.14 mmol, 0.14
3
mL) at room temperature. The progress of the reaction slowed after 1h. After 2 h, an additional
0
.14 mL of LiHBEt solution was added. When the remaining starting material had been
3
consumed (3h), the reaction was cooled to 0 °C and quenched by addition of water. The aqueous
layer was extracted with hexanes (2 × 1 mL), and the combined organic layer was dried with
Na SO then concentrated under reduced pressure. The crude product was purified by flash
2
4
chromatography using hexanes:ethyl acetate (6:1) as mobile phase to afford 0.0242 g (~100%) of
1
the desired product 9 as clear oil: R 0.70 (hexanes:EtOAc 2:1); H NMR (400 MHz, CDCl , δ )
f
3
4.51 (br s, 1H), 3.11 (br q, J = 6.6 Hz, 2H), 1.55–1.38 (m, 2H), 1.44 (s, 9H), 1.32–1.21 (m, 6H),
13
0
.88 (t, J = 6.7 Hz, 3H); C NMR (100 MHz, CDCl , δ ) 156.0, 79.0, 40.6, 31.5, 30.0, 28.4, 26.5,
3
4
2
22.6, 14.0. NMR data are consistent with those reported previously.
O
t-BuO
N
H
5ꢀ(tertꢀbutoxycarboxamido)pentane (11). A solution of 5ꢀ(tertꢀbutoxycarboxamido)pentyl
alcohol (10, 0.0976 g, 0.480 mmol) and DMAP (2.1 equiv, 1.0106 mmol, 0.1234 g) in 5 mL of
DCM was treated with diphenyl phosphoryl chloride (2.0 equiv, 0.9839 mmol, 0.20 mL) at room
temperature. After 2 h, the reaction was evaporated under reduced pressure, and the residue was
dissolved in ethyl acetate. The solution was washed with water, 1N NaHCO and brine. After
3
drying with Na SO , the organic layer was evaporated in vacuo. The crude phosphoric acid 5ꢀ
2
4
(tertꢀbutoxycarboxamido)pentyl diphenyl ester was dissolved in THF (3 mL). To the stirred
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solution was added LiHBEt (1.0 M in THF, 1.7 equiv., 0.8362 mmol, 0.84 mL) at room
3
temperature. After 5h, TLC showed the presence of some unreacted starting material, so an
additional 0.14 mL of LiHBEt solution was added. When the remaining starting material had
3
0
1
2
3
4
5
6
7
8
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0
1
2
3
4
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been consumed (14h), the reaction was cooled to 0 °C and quenched by addition of water. The
aqueous layer was extracted with hexanes, and the combined organic layer was dried with
Na SO and concentrated under reduced pressure. The crude product was purified by flash
2
4
chromatography using hexanes:ethyl acetate (4:1) to afford 0.0648 g (0.3460 mmol, 72%) of the
1
desired product 11 as a clear oil: R 0.75 (hexanes/ EtOAc 2/1); H NMR (400 MHz, CDCl , δ)
f
3
4.55 (br s, 1H), 3.09 (br q, J = 6.6 Hz, 2H), 1.50–1.38 (m, 2H), 1.43 (s, 9H), 1.36–1.20 (m, 4H),
1
3
0.88 (t, J = 7.0 Hz, 3H); C NMR (100 MHz, CDCl , δ) 156.2, 79.2, 40.8, 29.9, 29.2, 28.6, 22.5,
3
43
14.2. NMR data are consistent with those reported previously.
O
(Z)ꢀ1ꢀbenzyloxyꢀ2ꢀbutene (13). To a roundꢀbottom flask containing a stir bar, (Z)ꢀ4ꢀ
39
benzyloxybutꢀ2ꢀenꢀ1ꢀol (12, 0.1590 g, 0.8928 mmol; prepared as described ) and DMAP (20
mol%, 0.1785 mmol, 0.0218 g) was added 10 mL of DCM followed by triethylamine (1.1 equiv.,
0.9821 mmol, 0.14 mL) and diphenyl phosphoryl chloride (1.2 equiv, 1.0714 mmol, 0.22 mL).
The reaction was stirred at room temperature for 2 h, after which the solvent was removed under
reduced pressure. Ethyl acetate was added, and the organic layer was sequentially washed with
water, 1N NaHCO and brine. The organic layer was dried with Na SO , and the solvent was
3
2
4
evaporated under reduced pressure. The crude material was dissolved in 6 mL of THF, treated
with LiHBEt (1.0 M in THF, 1.7 equiv., 1.5178 mmol, 1.5 mL) and stirred at room temperature.
3
After 6 h the reaction was quenched by addition of water, and the mixture was extracted with
EtOAc (5×). The combined organic layer was dried with Na SO , and the solvent was removed
2
4
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under reduced pressure. Purification by flash chromatography using hexanes:EtOAc gave
unreacted starting material (0.0132 g, 0.0740 mmol) along with pure butꢀ2ꢀenyloxymethylꢀ
benzene (0.0856g, 0.5276 mmol) as clear oil in 59% yield (64% based on recovered starting
10
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1
material): R 0.42 (hexanes:EtOAc 8:1); H NMR (400 MHz, CDCl , δ) 7.39–7.27 (m, 5H),
f
3
5.75–5.60 (m, 2H), 4.53 (s, 2H), 4.10 (dp, J = 6.3, 1.0 Hz, 1H), 1.66 (br d, J = 7.5 6.0Hz, 3H);
13
C NMR (100 MHz, CDCl , δ) 138.6, 128.6, 128.3, 128.0, 127.8, 127.0, 72.3, 65.6, 13.4. NMR
3
4
4
data are consistent with those reported previously.
OP(O)(OPh)2
O
BnO
BnO
OMe
OBn
Methyl 2,3,4ꢀtriꢀOꢀ(benzyl)ꢀ
To a roundꢀbottom flask containing a stir bar, methyl 2,3,4ꢀtriꢀOꢀ(benzyl)ꢀβꢀDꢀglucopyranoside
0.0427 g, 0.0919 mmol) and DMAP (2.0 equiv, 0.1838 mmol, 0.224 g) was added DCM (1.0
mL) at room temperature under nitrogen. Diphenyl phosphoryl chloride (2.0 equiv, 0.1838 mmol,
.4 mL) was added, and the reaction mixture was stirred at room temperature. After completion
βꢀdꢀglucopyranoside, diphenyl phosphate (diphenyl phosphate of 14).
(
0
of the reaction (2h) the solvent was evaporated under reduced pressure. The residue was
dissolved in ethyl acetate and washed with water. The water layer was extracted with ethyl
acetate (3×), and the combined organic layer was washed with 1N NaHCO , water and brine,
3
then dried over Na SO . Evaporation of the solvent under reduced pressure gave the crude
2
4
product, which was purified by flash chromatography using hexanes:ethyl acetate (3:1) to afford
1
0.0555 g (0.0797 mmol, 87%) of the desired compound: H NMR (400 MHz, CDCl , δ) 7.37–
3
7
.12 (m, 25H), 4.92 (dd, J = 11.0, 6.9 Hz, 2H), 4.78 (dd, J = 10.8, 4.3 Hz, 2H), 4.70 (d, J = 11.0
Hz, 1H), 4.53 (ddd, J = 10.0, 6.4, 1.0 Hz, 1H), 4.47 (d, 1H, J = 10.8 Hz), 4.40–4.33 (m, 1H),
4
.31 (d, 1H, J = 7.8 Hz), 3.65 (t, 1H, J = 3.4 Hz), 3.51 (s, 3H), 3.55–3.46 (m, 2H), 3.40 (dd, J =
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13
7
.9, 0.9 Hz, 1H); C NMR (100 MHz, CDCl , δ) 150.65 (d, J = 7.4 Hz), 150.58 (d, J = 7.2 Hz),
3
138.53, 138.49, 137.8, 129.91, 129.87, 128.6, 128.53, 128.51, 128.22, 128.17, 128.08, 127.95,
27.83, 127.80, 125.55 (d, J = 4.8 Hz), 125.50 (d, J = 4.8 Hz), 120.32 (d, J = 5.0 Hz), 120.25 (d,
1
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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8
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J = 4.8 Hz), 104.6, 84.5, 82.3, 77.1, 75.8, 75.2, 74.9, 73.5 (d, J = 7.9 Hz), 67.7 (d, J = 5.5 Hz),
+
57.1; HRMS (ESI–FTICR) calcd for C H O PNa [M+Na] 719.23859, found 719.23795.
4
0
41
9
O
BnO
OMe
BnO
OBn
Methyl 6ꢀdeoxyꢀ3,4,5ꢀtriꢀOꢀbenzylꢀ
βꢀdꢀglucopyranoside (15). To a stirred solution of methyl
2
,3,4ꢀtriꢀOꢀ(benzyl)ꢀβꢀDꢀglucopyranoside, diphenyl phosphate (diphenylphosphate of 14, 0.0383
g, 0.0550 mmol) in THF (0.38 mL) and oꢀxylene (0.1 mL) was added LiEt BH (1.0 M solution
3
in THF; 1.8 equiv, 0.1 mmol, 0.1 mL) at room under nitrogen. After 1 h, TLC showed unreacted
starting material, so another 0.15 mL of LiEt BH solution was added. After 4 h, the reaction was
3
complete, as evidenced by TLC, and it was quenched by addition of water, then extracted with
ethyl acetate (3×). The combined organic layer was dried with Na SO , and the solvent was
2
4
evaporated under reduced pressure. Purification of the residue by flash chromatography using
hexanes:ethyl acetate (8:1) afforded 0.0173 g (0.0386 mmol, 70%) of the product as colorless
1
oil: R 0.28 hexanes:EtOAc 8:1); H NMR (400 MHz, CDCl , δ) 7.37–7.28 (m, 15H), 4.94 (d, J
f
3
= 10.7 Hz, 1H), 4.93 (d, J = 11.0 Hz, 1H), 4.89 (d, J = 10.9 Hz, 1H), 4.81 (d, J = 10.8 Hz, 1H),
4
.72 (d, J = 11.0 Hz, 1H), 4.64 (d, J = 10.8, 1H), 4.30 (d, J = 7.8 Hz, 1H), 3.62 (t, J = 9.2 Hz,
1
3
1
H), 3.58 (s, 3H), 3.45–3.37 (m, 2H), 3.21 (t, J = 9.2 Hz, 1H), 1.33 (d, J = 6.0 Hz, 3H); C
NMR (100 MHz, CDCl , δ) 138.8, 138.3, 128.7, 128.6, 128.31, 128.27, 128.1, 128.06, 127.9,
3
1
04.8, 84.6, 83.6, 82.8, 75.9, 75.6, 74.9, 71.3, 57.3, 18.1. NMR data are consistent with those
4
5
reported previously.
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OP(O)(OPh)2
Phosphoric acid 1ꢀmethylheptyl diphenyl ester. To a roundꢀbottom flask containing a stir bar,
(±)ꢀ2ꢀoctanol (0.3 g, 2.304 mmol) and DMAP (2 equiv, 4.608 mmol, 0.5630 g) was added DCM
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
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56
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60
(
38 mL) under nitrogen. Diphenyl chlorophosphate (2.0 equiv, 5.630 g, 0.95 mL) was added at
room temperature to the stirred solution After 1.5 h, the reaction mixture was concentrated under
reduced pressure. The residue was taken up in EtOAc, washed with water, 1N NaHCO , and
3
brine, then dried with Na SO . Removal of the solvent under reduced pressure afforded the crude
2
4
product, which was purified by flash chromatography using hexanes:ethyl acetate (4:1) to give
the desired compound as colorless oil (0.7515 g, 2.0736 mmol) in 89% yield: R 0.74
f
1
hexanes:EtOAc 2:1); H NMR (400 MHz, CDCl ) δ 7.33 (br t, J = 7.6 Hz, 4H), 7.23 (br d, J =
3
8
.1 Hz, 4H), 7.17 (br t, J = 7.3 Hz, 2H), 4.73 (sep, J = 6.5 Hz, 1H), 1.73–1.62 (m, 1H), 1.56–1.48
13
(m, 1H), 1.34 (d, J = 6.2 Hz, 3H), 1.32–1.14 (m, 8H), 0.86 (t, 3H, J = 6.9 Hz); C NMR (100
MHz, CDCl ) δ 150.88 (d, J = 7.2 Hz), 150.86 (d, J = 7.2 Hz), 129.8, 125.3, 120.29 (d, J = 5.1
3
Hz), 120.26 (d, J = 5.0 Hz), 78.7 (d, J = 6.7 Hz), 37.5 (d, J = 6.4 Hz), 31.8, 29.1, 25.1, 22.7, 21.7
(d, J = 3.3 Hz), 14.2; HRMS (ESI–QTOF) calcd for C H NaO P [M+Na] 385.1545, found
20 27 4
3
85.1545.
Octane. To a stirred solution of phosphoric acid 1ꢀmethylheptyl diphenyl ester (0.0334 g, 0.0922
mmol) in THF (0.6 mL) was added dropwise at room temperature LiEt BH (1.0M in THF, 2.2
3
equiv, 0.2027 mmol, 0.20 mL). Upon completion of the reaction in 4h, the reaction was
quenched with saturated aqueous NH Cl, and the aqueous layer was extracted with DCM (3×).
4
The combined organic layer (the total volume 4.5 mL) was dried with Na SO . An aliquot of 38
2
4
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2
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5
5
5
5
5
5
5
6
ꢀ
L was diluted with DCM to 2 mL, and the solution was subjected to GC analysis using decane
as internal standard. Octane was produced in 44% yield.
Me
Me
H
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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8
9
0
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2
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7
8
9
0
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9
0
Me
H
H
H
(
PhO) P(O)O
2
H
(3
19, 0.1000 g, 0.2655 mmol) and DMAP (1.0 equiv, 0.2655 mmol, 0.0324g) in DCM (7.5 mL)
was added triethylamine (2.2 equiv, 0.5841 mmol, 0.08 mL) and diphenyl phosphoryl chloride
2.4 equiv., 0.6372 mmol, 0.13 mL) at room temperature. Upon completion of the reaction (3h),
α,5β)ꢀCholanꢀ3ꢀol, diphenyl phosphate (20). To a stirred solution of (3α,5β)ꢀcholaneꢀ3,24ꢀdiol
(
(
the solvent was removed under reduced pressure. The residue taken up in ethyl acetate, then
washed with water, 1N NaHCO and brine. After drying with Na SO , the solvent was removed
3
2
4
in vacuo. The crude bisꢀphosphate was dissolved in 1.6 mL of THF and treated with LiEt BH
3
(1.0 M solution in THF; 1.7 equiv, 0.4513 mmol, 0.45 mL) at room temperature under nitrogen.
After 3 h, TLC showed a trace of the starting material, so another 0.20 mL of LiEt BH solution
3
was added. After an additional 1.5 h, the reaction was quenched by addition of water and
extracted with ethyl acetate (5×). The combined organic layer was washed with brine and dried
with Na SO before the solvent was removed under reduced pressure. The residue was
2
4
repeatedly dissolved in methanol and evaporated under reduced pressure to remove residual
borate. Purification by flash chromatography (hexanes:ethyl acetate, 5:1) afforded 0.0966 g
(61%) of the product as colorless oil: R 0.82 hexanes:EtOAc 5:1); IR 3067, 2937, 2865, 1591,
f
–
1 1
1489, 1193, 1015, 951, 689 cm ; H NMR (400 MHz, CDCl , δ) 7.36–7.32 (m, 4H), 7.25–7.16
3
(m, 6 H), 4.50–4.63 (m, 1H), 2.06–1.94 (m, 2H), 1.90–1.78 (m, 4H), 1.71–1.62 (m, 1H), 1.61–
1.52 (m, 2H), 1.46–1.32 (m, 8H), 1.31–0.95 (m, 11H), 0.92 (s, 3H), 0.91 (d, J = 6.6 Hz, 3H),
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0
.88 (t, J = 7.0 Hz, 3H), 0.65 (s, 3H); C NMR (100 MHz, CDCl , δ) 150.8 (d, J = 7.2 Hz),
3
129.9, 125.3, 120.30 (d, J = 5.0 Hz), 120.27 (d, J = 5.0 Hz), 81.3 (d, J = 6.6 Hz), 56.5, 56.5, 42.8,
4
2.2, 40.6, 40.3, 38.5, 35.9, 35.7, 35.1, 34.6, 34.1 (d, J = 4.4 Hz), 28.6 (d, J = 4.4 Hz), 28.5, 27.1
10
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53
54
55
56
57
58
59
60
2
6.4, 24.4, 23.4, 21.0, 19.4, 18.8, 14.8, 12.2; HRMS (ESI–QTOF) calcd for C H NaO P
3
6
51
4
[M+Na] 601.3423, found 601.3444.
Me
Me
H
Me
H
H
H
HO
H
(3α β)ꢀCholanꢀ3ꢀol (21). To a solution of (3α,5β)ꢀcholaneꢀ3,24ꢀdiol (0.0550 g, 0.1517 mmol) in
,5
1.5 mL of THF was added dropwise at room temperature nꢀBuLi (2.5M in hexanes, 2.1 equiv,
0.3212 mmol, 0.13 mL). The reaction mixture was stirred for 30 min at room temperature. Some
white precipitate formed, and additional THF (0.5 mL) was added. After 30 min, the reaction
mixture was treated with diphenyl chlorophosphate (2.1 equiv, 0.3212 mmol, 0.067 mL) at room
temperature, which led to dissolution of the precipitate. After 2 h at room temperature, LiEt BH
3
(1.0 M in THF, 1.32 equiv, 0.2 mmol, 0.2 mL) was added, and the mixture was left to stir
overnight. The reaction was quenched with saturated aqueous NH Cl and extracted with ethyl
4
acetate (7×). After drying with Na SO , the solvent was removed in vacuo. The crude phosphate
2
4
was dissolved in 1.5 mL of dry toluene, cooled to 0 °C and treated with sodium bis(2ꢀ
methoxyethoxy)aluminum hydride (65 wt. % solution in toluene, 0.28 mL), and the mixture was
gradually warmed to room temperature. The reaction was quenched with water, followed by
slow addition of 10% HCl at 0 °C until all solids dissloved. The organic layer was separated, and
the aqueous layer was extracted with DCM (3×). After drying with Na SO , the combined
2
4
organic layer was concentrated in vacuo to afford cholanol 21 as colorless solid 0.0448 g (0.1242
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
mmol, 82%): H NMR (400 MHz, CDCl , δ) 3.68–3.58 (m, 1H), 1.98 (dt, J = 12.0, 3.0, 1H),
3
1.92–1.71 (m, 4H), 1.70–0.94 (m, 24H), 0.93 (s, 3H), 0.90 (d, J = 6.6 Hz, 3H), 0.87 (t, J = 7.0 Hz,
13
3
H), 0.65 (s, 3H); C NMR (100 MHz, CDCl , δ) 72.1, 56.7, 56.6, 42.9, 42.3, 40.7, 40.4, 38.5,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
6.7, 36.1, 35.8, 35.6, 34.8, 30.8, 28.5, 27.4, 26.6, 24.5, 23.6, 21.0, 19.4, 18.8, 14.8, 12.2. NMR
1
5
data are consistent with those reported previously.
Acknowledgements
This work was sponsored in part by the Laboratory Directed Research and Development
Program of Oak Ridge National Laboratory, managed by UTꢀBattelle, LLC, for the U. S.
Department of Energy under contract number DEꢀAC05ꢀ00OR22725 and in part by the
University of Illinois at Chicago. We thank Todd Schweir, Ilya Seregin and Stepan Chuprakov
for assistance with GCꢀMS analyses.
1
13
Supporting Information. H and C spectra in a PDF file for the following (includes all novel
componds): 5, 6, 7, 9, 11, 13, 15, 20, 21 and the diphenyl phosphates of 6, 8, 14 and 2ꢀoctanol.
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45. Bernet, B.; Vasella, A. Helv. Chim. Acta 1979, 62, 1990.
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