Multi-gram-scale synthesis of a versatile syn-anti stereotriad by a short and cost-effective route

Article abstract of DOI:10.24820/ark.5550190.p010.902

The polyketide family of natural products includes numerous biologically important molecules that exhibit a variety of complex structures. The biosynthesis of these diverse structures relies on the iterative assembly of individual segments controlled by t

Full text of DOI:10.24820/ark.5550190.p010.902

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Organic Chemistry
Multi-gram-scale synthesis of a versatile syn-anti stereotriad
by a short and cost-effective route
David J. Galler, Gabriela C. Bermudez, and Kathlyn A. Parker*
Department of Chemistry, State University of New York at Stony Brook, Stony Brook,
New York 11794, USA
Email: Kathlyn.parker@stonybrook.edu
Dedicated to Professor George A. Kraus in tribute to his many contributions
to synthetic methodology and total synthesis
Received 02-05-2019
Accepted 03-22-2019
Published on line 04-24-2019
Abstract
The polyketide family of natural products includes numerous biologically important molecules that exhibit a
variety of complex structures. The biosynthesis of these diverse structures relies on the iterative assembly of
individual segments controlled by the enzymes of the polyketide synthase (PKS) family. In the synthesis
laboratory, access to stereospecifically-prepared ketide building blocks can be both challenging and cost-
limiting. We report an efficient, multigram-scale synthesis of the syn-anti synthon (2S,3R,4S)(E)-6-cyclohexyl-3-
[(4-methoxybenzyl)oxy]-2,4-dimethylhex-5-en-1-ol from the commercially available cyclohexane-
carboxaldehyde in excellent overall yield and purity.
Keywords: Polyketides, polypropionates, enantioselection, synthon, catalysis
DOI: https://doi.org/10.24820/ark.5550190.p010.902
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Introduction
The polyketides are complex and diverse natural products.1,2 Many are in drug trials1 and clinical use.2 About
22% of prescription drugs that are derived from natural products contain polyketide units.3 The large number
of asymmetric centers in most of these substances, often in contiguous runs, pose major obstacles to their
synthetic construction.
The asymmetric synthesis of polyketide compounds is performed in nature by polyketide synthetases
(PKSs) which direct the necessary aldol couplings, reductions, and, in some cases, dehydrations.4-6 An often-
used strategy in the laboratory synthesis of polyketides is the iterative coupling of small chiral building blocks.6
Such syntheses, which have largely focused on stereospecificity, can be costly on a large scale.7,8 For example,
the practical total synthesis of discodermolide (Figure 1), a marine polyketide, remains a formidable challenge.
We describe the multi-gram, catalytic, asymmetric preparation of stereotriad (1a) by a six-step route that
offers convenience and promises further scalability.
Figure 1. The natural polyketide (+)-discodermolide.
In earlier work on an approach to discodermolide, we designed the chiral syn-anti stereotriad (1) and
reported a small-scale, five-step, catalytic asymmetric preparation of the syn-anti stereotriad building blocks
(1b) and (1c).9-11 These synthons and their equivalents offer particularly attractive options for extending the
polyketide chain in both directions. Of special note is the potential for ozonolysis as a method of liberating an
aldehyde at one terminus.
To date, the syn-anti stereotriad unit (2) from Leighton,12,13 (3) from Smith,14,15 and the identical Novartis-
Smith-Paterson16-20 unit are the only examples of syn-anti building blocks that have been prepared on multi-
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gram scales. Each of these substances is easily modifiable at each terminus for ease of continued synthetic
elaboration.
We report the large-scale synthesis of synthon 1a using Carreira’s asymmetric addition reaction21-24 as a
key step in an expansion of our previous approach. This preparation is outlined in Scheme 1.
OH
OH
(-)-N-methylephedrine
Zn(OTf)2, NEt3, propyne
toluene
CHO
H2/Lindlar
cyclohexane
quant.
97%
6
5
4
O
Br
OH
NaH, NaI
t-BuLi
THF
80%
THF
84%
8
7
Cl
9-BBN dimer
2N NaOH
30% H2O2
OPMB
NaH, NaI
MeO
THF
95%
THF
90%
9
OPMB
OH
1a
Scheme 1. The synthesis of synthon 1a (54% overall yield, 95% ee).
Results and Discussion
Our previously reported approach to stereotriad (1) was modified to improve the yield and ease of handling.
In the earlier work,9-11 (-)-N-methylephedrine was used as a chiral auxiliary to direct a propenylation of
cyclohexanecarboxyaldehyde (4) to produce the alcohol (6) in one step. These reaction conditions proved to
be highly moisture sensitive, difficult to maintain in large batches, and challenging to reproduce. This step was
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replaced by a two-step procedure: Carreira propynylation and hydrogenation. The Carreira reaction21-24
afforded the alcohol (5) in 97% yield with 95% ee.
We note, however, that zinc triflate is an expensive source of zinc(II) ion. Thus, other zinc salts were
considered to reduce the cost of this step while retaining yield and ee. These results (Table 1) highlight the
clear advantage of zinc triflate over zinc bromide and zinc chloride. Despite the variation in overall yield
depending on the zinc salt, the overall ee of the product remained unaffected. Although we were unable to
find an acceptable alternative to zinc triflate, we were able to reduce the amount of salt to 10 mol % without
sacrificing yield using extended reaction times. (–)-N-Methylephedrine can be recovered, quantitatively, from
aqueous extraction.25
Table 1. Summary of the optimization of Carreira’s conditionsa
.
Salt
Mol %
100
100
100
60
Reaction time
48 h
Yield (%)
Zinc(II) chloride
Zinc(II) bromide
Zinc(II) triflate
Zinc(II) triflate
Zinc(II) triflate
36
45
96
97
94
48 h
48 h
48 h
10
7 d
a
All reactions were performed with toluene as the solvent. The ee, as determined by
Mosher ester analysis, was unaffected by the Zn(II) source.
The subsequent reduction of alcohol (5) with Lindlar’s catalyst provided the necessary (Z)-olefinic alcohol
(6) in quantitative yield. Formation of ether (7) was performed under Finkelstein conditions.26 Our synthetic
intermediate syn diad (8) was easily isolated after a [2,3]-Wittig rearrangement of 7.27-33 Optimum conditions
for this rearrangement required the use of excess t-BuLi (Table 2). This protocol afforded the rearranged 8
without side products.33 Unreacted starting material was easily recovered by chromatography.
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Table 2. Optimization of the [2,3]-Wittig rearrangementa
.
Base
Temperature
Yield (%)c
n-BuLi, t-BuOK
n-BuLi, t-BuOK, HMPA
n-BuLi, LDA
-78 ˚C to 0 ˚C
-78 ˚C to 0 ˚C
-78 ˚C to 0 ˚C
35
0
0
n-BuLi, t-BuOK
n-BuLi
-78 ˚C to 0 ˚C, then 0 ˚C to -78 ˚C
-78 ˚C to 0 ˚C
66
50
55
60
80
sec-BuLi
t-BuLib
t-BuLib
-78 ˚C to 0 ˚C
-78 ˚C to 0 ˚C
-90 ˚C to -20 ˚C
a.All reactions were performed with 100 mg of substrate (7) in THF under argon atmosphere
for 4h. b. No byproduct was observed. c Yields reflect product isolated following
chromatography.
Finally, alcohol (8) was converted to the desired syn-anti synthon (1a) by a two-step procedure, i.e.,
protection with p-methoxybenzyl chloride (PMB-Cl) followed by selective oxidation of the terminal olefin with
crystalline 9-borabicyclo[3.3.1]nonane (9-BBN).
We imagine that synthon (1a) may be incorporated into large polyketides through easily performed
transformations. 34-40
Conclusions
In summary, we have successfully completed a multi-gram asymmetric synthesis of the syn-anti synthon (1a)
in six steps in 54% overall yield with 95% ee. We envision this stereotriad to be a precursor to a variety of
synthetically useful compounds that contain contiguous stereochemical centers. We believe that the cost
effectiveness of this approach is advantageous for large-scale polyketide synthesis.
Experimental Section
General. Solvents were dried over calcium hydride. Thin-layer chromatography was performed on Agela
plates, 0.25mm thickness, 60Å F254. Plates were stained with 15-20% phosphomolybdic acid (PMA) or
visualized by UV (254 nm). Commercially-available reagents were purchased from Alfa Aesar. All NMR spectra
were recorded on Bruker 500 MHz and 700 MHz spectrometers. NMR solvents were purchased from
Cambridge Isotope Laboratories (Tewksbury, Massachusetts, USA). High-resolution mass spectra (HRMS) were
acquired with electrospray ionization (positive mode) at the Stony Brook University Mass Spectrometry Lab on
an Agilent LC-UV-TOF model G6224A oaTOF. IR spectra were collected on a Thermo Scientific Nicolet iS10 FTIR
spectrophotometer.
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(S)-1-Cyclohexylbut-2-yn-1-ol (5).23 Triethylamine (25.0 g, 246 mmol), Zn(OTf)2 (39.0 g, 107 mmol), and (-)-N-
methylephedrine (21.0 g, 117 mmol) were added to an argon-filled 2 L pressure vessel along with 1.2 L of dry
toluene. The mixture was stirred for 2 h at room temperature after which cyclohexanecarboxyaldehyde (20.3
g, 181 mmol) was added. The vessel was chilled to -78 °C in an acetone/dry ice bath. Propyne gas (9.8 g, 245
mmol) was added and the vessel was sealed with a Teflon screw cap. The reaction mixture was warmed to
room temperature and stirred for 72 h. The reaction was quenched with a saturated solution of NH4Cl. The
organic phase was washed three times with 500 mL saturated NH4Cl solution, dried over MgSO4, and
concentrated under reduced pressure to afford a clear, colorless oil. Yield: 26.6 g (97.0%).
(S)(Z)-1-Cyclohexylbut-2-en-1-ol (6).9 Alcohol 5 (20.0 g, 131 mmol) was dissolved in 200 mL of dry cyclohexane
and added to a 500 mL Parr shaker flask. Lindlar’s catalyst (1.67 g, 0.790 mmol) was added. The vessel was
then flushed with hydrogen and pressurized to 52.0 psi four times until the hydrogen uptake ceased. The
mixture was then filtered through Celite and washed through with cyclohexane. The filtrate was concentrated
under reduced pressure to afford a pale yellow oil. Yield: 22 g (quantitative).
(S)(Z)-{1-[(2-Methylallyl)oxy]but-2-en-1-yl}cyclohexane (7).9 Dry THF (300 mL) was added to a 500 mL argon-
flushed two-neck round-bottom flask which was cooled in an ice bath. Sodium hydride (60%, 29.0 g, 720
mmol) was slowly added into the reaction vessel and the reaction mixture was stirred for 15 minutes.
3-Bromo-2-methylpropene (32.4 g, 240 mmol), was then added, followed by the dropwise addition of alcohol
(6) (22.0 g, 143 mmol) in THF (10 mL). The reaction mixture was stirred for an additional 10 minutes then
sodium iodide (21.4 g, 143 mmol) was added. The solution was warmed to room temperature and left
overnight. The mixture was chilled in an ice bath and quenched with the slow addition of water until two
layers formed. The aqueous phase was then extracted three times with ether (300 mL portions). The
combined organic-phase solution was dried over MgSO4 and concentrated under reduced pressure. The crude
material was purified using column chromatography (silica gel, 20:1 hexanes:ethyl acetate) to afford a pale
yellow oil. Yield: 25.3 g (84%).
(3R,4S)(E)-6-Cyclohexyl-2,4-dimethylhexa-1,5-dien-3-ol (8).9 A flame-dried 500 mL three-neck round-bottom
o
flask was purged with argon and cooled to -90 C. tert-Butyllithium (100 mL, 160 mmol) was transferred into
an argon-purged addition funnel via cannula, then, slowly dripped into the reaction vessel over 20 minutes.
Ether (7) (11.0 g, 53.0 mmol) in dry THF (10 mL) was then added dropwise to the reaction vessel followed by
o
12-crown-4 (0.26 mL) and the mixture was stirred for 4h at -90 C. The reaction was quenched by slow drop-
wise addition of water and warmed to room temperature over 2 h. The aqueous phase was extracted three
times with ethyl acetate (100 mL portions). The combined organic solution was dried over anhydrous MgSO4
and concentrated under reduced pressure. The crude material was purified by column chromatography (silica
gel 20:1 hexanes:ethyl acetate) to afford product as a yellow oil. Yield: 8.55 g (78%).
(3R,4S)(E)-1-{[(6-Cyclohexyl-2,4-dimethylhexa-1,5-dien-3-yl)oxy]methyl}-4-methoxybenzene (9). Dry THF
(100 mL) was added to a 250 mL argon-flushed two-neck round-bottom flask and cooled in an ice bath.
Sodium hydride (60%, 1.72 g, 72.0 mmol) was slowly added to the reaction vessel and the resulting suspension
was stirred for 15 minutes. Alcohol (8) (3.00 g, 14.4 mmol) was dissolved in dry THF (15 mL) and added into
the reaction vessel followed by para-methoxybenzyl chloride (5.88 mL, 43.2 mmol). After 10 minutes of
stirring, sodium iodide (2.15 g, 14.4 mmol) was added and the reaction mixture was brought to room
temperature and left for 72 h. The reaction mixture was chilled in an ice bath and quenched by the slow
addition of water until two layers formed. The aqueous phase was extracted three times with ether (50 mL
portions). The combined organic solution was dried over MgSO4 and concentrated under reduced pressure.
The crude material was purified by column chromatography (silica gel, 20:1 hexane:ethyl acetate) to afford
1
the product as a pale yellow oil. Yield: 4.50 g (95.0%). Rf 0.66 (20 : 1 hexane : ethyl acetate) H-NMR (CDCl3,
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500 MHz): δ 7.25 (d, J 8 Hz, 2H), 6.87 (d, J 8 Hz, 2H), 5.30 (m, 1H), 5.12 (m, 1H), 4.94 (s, 1H), 4.82 (s, 1H), 4.44
(d, J 11 Hz, 1H), 4.15 (d, J 11 Hz, 1H), 3.80 (s, 3H), 3.34 (d, J 9 Hz, 1H), 2.28 (m, 1H), 1.84 (m, 1H), 1.64 (m, 8H),
1.19 (m, 3H), 1.05 (d, J 7 Hz, 3H), 0.99 (m, 2H). 13C-NMR (CDCl3, 125 MHz): δ 159.0, 143.7, 135.7, 131.0, 129.6,
129.4, 129.3, 114.6, 114.7, 113.7, 113.5, 87.7, 69.7, 55.3, 40.6, 39.5, 33.11, 33.08, 26.2, 26.1, 17.5, 17.1. IR cm-
1
(NaCl): 3069, 2923, 2850, 1650, 1613, 1586, 1513, 1449, 1370, 1348, 1301, 1247, 1207, 1172, 1109, 1073,
1039, 1011, 967, 899, 844, 821, 756, 637. HRMS (ESI+): C22H32O2 328.2402, calc for (M+H): 329.2475, found
329.2474.
(2S,3R,4S)(E)-6-Cyclohexyl-3-[(4-methoxybenzyl)oxy]-2,4-dimethylhex-5-en-1-ol (1a). In an argon-filled
round-bottom flask was added dry THF (25 ml) and ether (9) (1.00 g, 3.03 mmol). The solution was cooled to -5
°C, and 9-borabicyclo[3.3.1]nonane (9-BBN) dimer (1.48 g, 6.06 mmol) in THF (5 mL) was added dropwise. The
reaction mixture was warmed to room temperature and tracked by TLC. The reaction was complete after 12 h,
and the mixture was cooled back to -5 °C. Over 20 minutes, 2N NaOH (18 mL, 36 mmol) was added followed
by 30% H2O2 (18 mL). The reaction mixture was warmed to room temperature and left to stir for 5 h, then
diluted with ether (50 mL) and washed three times with sat. NH4Cl (25 mL portions). The organic solution was
dried over MgSO4, filtered, and concentrated under reduced pressure. The crude oil was purified by column
chromatography (silica gel, 10:1 hexane:ethyl acetate) to afford a clear colorless oil. Yield: 954 mg (90%). Rf
0.15 (10:1 hexane:ethyl acetate) 1H-NMR (CDCl3, 500 MHz): δ 7.28 (d, J 8 Hz, 2H), 6.89 (d, J 8 Hz, 2H), 5.42 (m,
2H), 4.61 (d, J 11 Hz, 1H), 4.48 (d, J 11 Hz, 1H), 3.81 (s, 3H), 3.72 (dd, J 8 Hz, 3 Hz, 1H), 3.56 (d, J 6 Hz, 1H), 3.26
(t, J 6 Hz, 1 H), 2.82 (s, 1H), 2.47 (m, 1H), 1.92 (m, 3H), 1.71 (m, 6H), 1.52 (m, 3H), 1.29 (m, 2H), 1.17, (tt, J 12
Hz, 3Hz, 1H), 1.09 (d, J 7 Hz, 3H), 1.06 (m, 1H), 1.00 (d, J 7 Hz, 3H) 13C-NMR (CDCl3, 125 MHz): δ 159.2, 136.1,
130.9, 129.4, 88.9, 74.7, 66.0, 55.2, 40.7, 39.8, 37.2, 34.7, 33.1, 33.0, 27.4, 26.1, 26.0, 22.6, 15.5. IR cm-1
(NaCl): 3418, 2919, 2236, 2061, 1878, 1739, 1613, 1586, 1514, 1448, 1348, 1301, 1247, 1173, 1036, 975, 892,
822, 757, 733. HRMS (ESI+): C22H34O3 346.2508, calc for (M+H): 347.2581, found 347.2583
Acknowledgements
D.J.G. and G.C.B. were Fellows of the Graduate Assistance in Areas of National Need (GAANN) Program of the
US Department of Education, P200A100044 and P20A120094. We thank Professor Francis Johnson (Stony
Brook University) for his continued mentorship during this project. We extend thanks to Francis Picart, Fang
Liu, and James Marecek from the NMR Facilities at Stony Brook, and Béla Ruzsicska from ICB&DD Mass
Spectrometry Laboratory for facilitating instrumental setup and data acquisition.
Supplementary Material
Supplementary data associated with this article can be found in the online version.
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