Large-scale preparation of key building blocks for the manufacture of fully synthetic macrolide antibiotics

Article abstract of DOI:10.1038/ja.2017.116

Key building blocks for the production of fully synthetic macrolides have been scaled-up in first time pilot plant and kilo-lab campaigns. These building blocks have supported the discovery of new macrolide antibiotics as well as ongoing preclinical studies.

Full text of DOI:10.1038/ja.2017.116

The Journal of Antibiotics (2017), 1–8
2017 Japan Antibiotics Research Association All rights reserved 0021-8820/17
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ORIGINAL ARTICLE
Large-scale preparation of key building blocks for the
manufacture of fully synthetic macrolide antibiotics
Philip C Hogan1, Chi-Li Chen1, Kristen M Mulvihill1, Jonathan F Lawrence1, Eric Moorhead1, Jens Rickmeier2
and Andrew G Myers2
Key building blocks for the production of fully synthetic macrolides have been scaled-up in first time pilot plant and kilo-lab
campaigns. These building blocks have supported the discovery of new macrolide antibiotics as well as ongoing preclinical
studies.
The Journal of Antibiotics advance online publication, 11 October 2017; doi:10.1038/ja.2017.116
INTRODUCTION
reaction of N-chlorosulfonyl isocyanate and formic acid with benzoin
All members of the macrolide antibiotic class that are approved for in N,N-dimethylacetamide (DMA) as solvent. A general preparation of
human use are manufactured by semisynthetic modification of the the latter reagent in the literature describes the addition of formic acid
natural product erythromycin (1).1,2 It is evident that the pace of to neat N-chlorosulfonyl isocyanate, with subsequent additions of
discovery of novel macrolide antibiotics by semisynthesis has slowed as DMA and 11 to the sequence.10 After extractive workup, a mixture of
routes have lengthened,3,4 while at the same time once important 14 and the non-cyclized intermediate 12 is obtained. Further conver-
agents such as clarithromycin5 (2) and azithromycin6 (3, Figure 1, sion of the remaining 12–14 is accomplished by action of p-
both approved in 1991)7 currently face widespread resistance within toluenesulfonic acid in refluxing toluene with azeotropic removal of
modern clinical isolates, diminishing their efficacy. Seiple et al.8 have water. In our hands, yields as high as 85% could be achieved after
recently described a broad and general platform for the synthesis of isolation of 14 from a re-slurry in t-butyl methyl ether (MTBE). Upon
macrolide scaffolds of various ring sizes and substitution patterns, preliminary evaluation of the process, we observed that a significant
which to date has provided 41400 individual fully synthetic antibiotic exotherm occurred during addition of formic acid to neat N-
candidates for evaluation. To facilitate both the discovery and eventual chlorosulfonyl isocyanate. Furthermore, the mixture became hetero-
manufacture of any given fully synthetic macrolide candidate, we have geneous in the process, leading to incomplete mixing. On one
investigated and here report our successful campaigns to provide on occasion during the subsequent addition of DMA, a violent exotherm
scale the essential building blocks 4–7 that we use to assemble, among took place, resulting in partial ejection of the reactor contents. We
other macrolides, the 15-membered aza-ketolide scaffold 10, depicted surmise that the heterogeneous reaction conditions led to incomplete
in Figure 2. Details of these early, fit-for-purpose manufacturing mixing, and therefore incomplete reaction, during the first stage and
campaigns, providing building blocks 4–7 in multi-hundred-gram to that the subsequent addition of DMA facilitated the mixing and
multi-kilogram quantities, are provided below.
reaction of the unreacted starting materials. We were encouraged to
explore an alternative preparation of 14 pursuing the report of
Mclaughlin et al.11 describing an alternative means to prepare
sulfamylimines. Accordingly, to a solution of t-butanol (t-BuOH,
RESULTS AND DISCUSSION
Pseudoephenamine glycinamide 4
To prepare (R,R)-pseudoephenamine glycinamide (building block 4), 1.35 equiv.) in tetrahydrofuran (THF) was charged N-chlorosulfonyl
it was necessary first to establish a preferred route to the versatile isocyanate (1.25 equiv.) maintaining an internal temperature below 0 °C.
chiral auxiliary (R,R)-pseudoephenamine (18). Although a large-scale Benzoin (11, 1 equiv.) was then added as a solid, followed by
route to this substance has been previously described,9 we explored the triethylamine (Et3N, 1.45 equiv.). The resultant N-tert-butoxycarbo-
alternative sequence depicted in Scheme 1 in light of two features of nyl-protected sulfamate 13 was isolated by addition of water directly to
the plan: its use of the highly practical starting material benzoin (11), the reaction mixture followed by collection of the product, which had
and the existence of a prior report defining conditions to execute a precipitated, by filtration. After vacuum drying, 13 was transformed
dynamic kinetic asymmetric reduction of the racemic sulfamylimine into 14 by refluxing a suspension of 13 in toluene in the presence of
14 to furnish product 15 with high enantioselectivity and catalytic p-toluenesulfonic acid (0.03 equiv.) with azeotropic removal
diastereoselectivity.10 We evaluated two different methods to prepare of water using a Dean–Stark apparatus. The material obtained after
the sulfamylimine 14. Initially, we made use of the product of the workup and re-slurry with MTBE was comparable in quality to that
1Process Chemistry, Macrolide Pharmaceuticals Inc., Watertown, MA, USA and 2Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA
Correspondence: Dr PC Hogan, Process Chemistry, Macrolide Pharmaceuticals Inc., 480 Arsenal Way, Suite 130, Watertown, MA 02472, USA.
E-mail: hoganphilip@gmail.com
Received 3 July 2017; revised 31 July 2017; accepted 17 August 2017

Large-scale production of fully synthetic macrolides
PC Hogan et al
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Figure 1 Representative macrolide antibiotics.
Figure 2 Building blocks and their assembly product, a 15-membered aza-ketolide antibiotic.
Scheme 1 Preparation of pseudoephenamine (18) by catalytic asymmetric transfer hydrogenation.
obtained by the other method, albeit with a slightly diminished yield side products arising from beta-elimination of the C-O bond within
(~75%), but offered the welcome advantage of being easily controlled
and therefore safer. The kinetic dynamic asymmetric transfer hydro-
genation of 14 to provide 15 was then investigated. We quickly learned
that, in our hands, to permit low catalyst loadings (0.0005 equiv.), it
was necessary to first distill the triethylamine–formic acid complex. A
multi-hundred-gram run provided 15 in 97% yield after workup and
silica gel filtration. The sulfamate 15 was treated with di-tert-butyl
dicarbonate ((Boc)2O, 1.05 equiv.) and 4-(dimethylamino)pyridine,
0.045 equiv. (DMAP) in dichloromethane to provide the N-Boc
derivative 16 in 96% yield.8 Invertive displacement of the C-O bond
within 16 was most conveniently accomplished using a mixture of
cesium carbonate and formic acid followed by decomposition of the
intermediate sulfamate salt with citric acid; other, larger and more
16. Treatment of the crude formate ester 17 with Red-Al in toluene
with heating at 90 – 100 °C led to a mixture of products containing the
undesired dimethylamino product 19 as a major component. We
attributed the formation of 19 to the presence of the formate ester
within 17. When the formate ester within 17 was first cleaved in basic
methanol, subsequent reduction of the resultant Boc-protected amino
alcohol with Red-Al at 90– 100 °C provided (R,R)-pseudoephenamine
(18) in high purity after a heptane re-slurry of the material obtained
from aqueous workup (86%, three steps from 16). Although this route
provided our discovery team with hundreds of grams of the desired
auxiliary, we felt that as a manufacturing protocol the route was
lengthy and somewhat tedious, and several intermediates were poorly
basic carboxylate nucleophiles led to mixtures containing as impurities soluble, necessitating the use of large amounts of solvent.
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Scheme 2 Manufacture of pseudoephenamine (18) and glycinamide 4 using previously reported procedure.
We returned to the earlier described preparation of 18, which was extraction of organic-soluble materials, the aqueous layer was con-
attractive from the standpoint that it used cheap and readily available centrated and remaining water was removed azeotropically with 2-
reagents of high optical purity, obviating the need for the use of an propanol, leading directly to the precipitation of desosamine hydro-
expensive chiral catalyst.9 This route, depicted in Scheme 2, has been chloride 26, conveniently isolated by filtration after a re-slurry in
used for manufacturing of multi-kilogram amounts of 18. The route dichloromethane. This provided a smoother and more scalable
begins with the commercially available amino alcohol 20. The isolation of 26 than the previously reported trituration of crude 26
formamide derivative (21) was conveniently prepared by treatment with ethyl ether. After collection of the solids and drying, 10.4 kg of 26
of 20 with catalytic ammonium formate in formamide with heating at was obtained in high purity. The anomeric benzoate esters 27 were
150 °C. Inversion of the hydroxyl group within 21 to provide 22 was prepared by treatment of 26 with benzoic anhydride and triethylamine
achieved essentially by the method of Tishler and colleagues, with in dichloromethane as solvent. The activated glycosidic donor 5 was
slight modifications.12 In our hands, treatment of 21 with neat thionyl best obtained by treatment of the anomeric benzoate esters 27 with
chloride led to modest yields of 22, and the quench of almost neat thiopyrimidine and trimethylsilyl trifluoromethanesulfonate in
thionyl chloride produced large volumes of gas as well as a significant dichloromethane.15 In our hands, the use of boron trifluoride ethyl
exotherm. Alternatively, we found that use of acetonitrile as solvent etherate provided lower yields. A small amount of a side product,
provided 22 in good yield after hydrolysis, and the quench was a well- tentatively assigned as 28, was removed by filtration through a silica
controlled process. Formylation of the amino group within 22 with gel plug. As the free base of 5 is generally obtained as a foam after
formic acid and acetic anhydride proceeded uneventfully to afford 23 concentration, the donor 5 was most conveniently isolated on scale by
in 95% yield provided that a slight excess of formic acid relative to precipitation from acetone/toluene as the corresponding oxalate salt
acetic anhydride was used. Otherwise, small amounts of the corre- (the free base form is typically obtained as a foam upon concentration)
sponding acetamide were observed as a contaminant. Reduction of the in 99.8 % HPLC purity (sum of anomers).
formamide 23 provided (R,R)-pseudoephenamine (18) in 83% yield
and 100% ee after crystallization from heptane. An improved Silyl enol ether 7
procedure to make the glycinamide derivative 4 was also developed. The keto-ester 31 was manufactured using the practical and scalable
Treatment of 18 with the reagent derived from addition of pivaloyl cross-Claisen methodology reported by Zhang et al.16 (Scheme 4). Thus
chloride (PivCl) to N-Boc glycine (24) and triethylamine provided the the propionate ester 29 was added to a solution of lithium diisopro-
amide 25, conveniently recrystallized from 2:1 toluene–heptane in pylamide (1.03 equiv.) in THF maintaining an internal temperature of
95% yield. Cleavage of the Boc group within 25 provided 4, obtained o − 65 °C. A solution lithium bis(trimethylsilylamide) (1.02 equiv.) in
in pure form from a toluene re-slurry.13
THF was then added, maintaining an internal temperature of o− 65 °
C, followed by a solution of phenyl propionate (30) in THF. A
quenching solution of saturated ammonium chloride was then added.
Desosamine donor
We have developed a suitable manufacturing route to the desosamine After phase separation, the organics were washed with 2 N sodium
donor 5 by modification of literature protocols (Scheme 3).14 In the hydroxide followed by a water wash. This procedure was performed at
optimized sequence, erythromycin (1, 59 kg) was treated with 3 N the 4–4.5 kg scale of 29 twice, and the batches were combined without
hydrochloric acid (HCl, 125 kg), at a temperature of 85 °C for 6 h. purification for the preparation of 32. To a mixture of the combined
Toluene (45 kg) was added to the hot (85 °C) mixture and then the batches of crude 31 (13.5 kg, uncorrected), acetone (8.5 kg) and acetic
biphasic solution was allowed to cool to 25 °C whereupon dichlor- anhydride (22.5 kg) cooled to 0 °C was added sulfuric acid (7.4 kg)
omethane (250 kg) was added. Failure to follow this protocol of maintaining a temperature of o15 °C. The mixture was then stirred for
solvent additions led to thick unstirrable mixtures. This first step 4 h at 20 °C. After neutralization and workup, the product was distilled
differs from the original protocol reported using ethanol as a co- to provide 5.74 kg of 32 in 57% yield (two steps) in 99% purity (HPLC
solvent. Omission of ethanol from this procedure avoided the analysis). The silyl enol ether 7 has been prepared on ~ 300 g laboratory
formation of the corresponding ethyl glycoside of desosamine, a scale. This was achieved by adding the dioxinone 32 neat to a solution
deleterious side product. Additionally, the original procedure used of lithium diisopropylamide (1.2 equiv.) containing a small amount of
extensive extractions with chloroform, a solvent whose use is generally triethylamine hydrochloride (Et3N•HCl, 0.02 equiv.) as recommended
not considered acceptable for scale-up, to separate organic soluble by- by Collum and colleagues for reactions promoted by lithium
products from the aqueous solution containing desosamine. After diisopropylamide.17 Chlorotrimethylsilane (1.2 equiv.), distilled from
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Large-scale production of fully synthetic macrolides
PC Hogan et al
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Scheme 3 Preparation of the oxalate salt of 5.
Scheme 4 Manufacture of the silyl enol ether 7.
calcium hydride, was added neat at − 65 °C and the resultant mixture added maintaining a temperature of o15 °C. The alcohol 35 was
was allowed to stir for 2 h at this temperature. The mixture was allowed
to warm to 0 °C and distillation in vacuo of the solvent led to the
precipitation of inorganic salts. The mixture was further concentrated
from heptanes and the suspended solids removed by filtration through
a thin pad of Celite. Omission of the Celite as a filter aid led to slow
filtrations not suitable for scale-up. After concentration of the filtrate,
the residue was purified by high vacuum distillation to provide 7. We
typically observe the product to be contaminated with ~ 10% 32 (79%
yield corrected), presumably due to some hydrolysis of 7 by adventi-
tious moisture during processing.
isolated by vacuum distillation. Protection of the hydroxyl group
within 35 was accomplished using tert-butyl(chloro)diphenylsilane
(TBDPSCI) and imidazole (Im) to provide 36 in 87% yield. Oxidative
cleavage of the alkene within 36 was then achieved using catalytic
potassium osmate (1.5 mol%) and sodium periodate as the stoichio-
metric oxidant on a 6.5-kg scale. The final compound was purified by
a fit-for-purpose silica gel filtration to obtain 5.25 kg of 6 in 80% yield
and 98% ee (chiral HPLC).
In conclusion, we have preliminarily verified and demonstrated the
scalability of building blocks that have been used to discover and
manufacture on preclinical scales fully synthetic macrolide antibiotics.
We anticipate improving both the cost of goods and efficiency of the
processes described above as our program advances.
(R)-3-((tert-butyldiphenylsilyl)oxy)pentan-2-one (6)
The fit-for-purpose manufacturing route to the ketone 6 was
essentially performed without modification of the reported sequence
(Scheme 5).18 Thus a mixture of the ligand 34 (2.5 mol%) and
diethylzinc in hexanes (1.0 M, 2 equiv.) was prepared at a temperature
of o15 °C, and then the mixture was heated to a temperature of 35 °C
for 1 h to generate, in our experience, the most active catalyst;
incubation of diethylzinc and 34 at lower temperatures led to sluggish
reactions with methacrolein (33) or reactions that did not proceed
EXPERIMENTAL PROCEDURES
4,5-Diphenyl-5H-1,2,3-oxathiazole 2,2-dioxide (14)
To a solution of tert-butanol (420 ml, 4.44 mol, 1.35 equiv.) in anhydrous THF
(3.5 litres) was added N-chlorosulfonyl isocyanate (357 ml, 4.11 mol, 1.25
equiv.) keeping the temperature between − 10 and 0 °C. After 15 min, 11
(700 g, 3.3 mol, 1 equiv.) was added as a solid and then triethylamine (663 ml,
appreciably. After cooling, a solution of 33 in hexane (1 equiv.) was 4.77 mol, 1.45 equiv.) was added via addition funnel keeping the temperature
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equiv.) while stirring and maintaining a temperature of o25 °C. A solution of
16 (60 g, 160 mmol) was charged in DMF (300 ml) and a separate portion of
16 (273 g, 728 mmol) was charged as a solid. DMF (450 ml) was used as a rinse
to quantitate transfers. After stirring 19 h at 20 °C, the mixture was added to
20% w/w citric acid in water (4.75 litres) and ethyl acetate (2.75 litres). The
organics were separated and the aqueous layer was washed with MTBE
(500 ml). The combined organics were washed with saturated sodium
bicarbonate (1 litres), followed by consecutive washes of water (2 litres) and
saturated aqueous sodium chloride (1 litre). The organics were then concen-
trated in vacuo to give 17 as a solid. To the crude 17 suspended in methanol
(1.5 litres) was added potassium carbonate (50 g). The resultant mixture was
vigorously agitated at 20 °C for 1 h. The suspension was filtered through a thin
pad of Celite and the resultant Celite bed was washed with methanol (2 litres).
The combined filtrates were concentrated in vacuo. To the obtained solids were
added ethyl acetate (2.5 litres) and water (1 litre). The resultant organic phase
was separated, dried over sodium sulfate and concentrated in vacuo. To the
residue was added toluene (2.5 litres) and 500 ml was removed by distillation
on a rotary evaporator at reduced pressure. To this solution was added Red-Al
(290 ml, ~ 60% wt in toluene, 891 mmol) while keeping the temperature
between − 20 and 0 °C. The reaction was allowed to warm to 20 °C and Red-Al
(655 ml, 2.01 mol) was added while warming the reaction with a heating
mantle (set to 80 °C). After the addition, the temperature exceeded 80 °C and
went as high as 105 °C. The mantle was then removed, and cooled with a water
bath until the temperature fell below 80 °C. The mixture was maintained at 80 °C
for 3 h and then cooled in a dry ice/acetone bath. Methanol (280 ml) was added
keeping the temperature o30 °C. The reaction contents were added to mixture
of toluene (1 litre), Na/K tartrate tetrahydrate (850 g) and water (2 litres). The
mixture was stirred overnight. The organics were separated and the aqueous
phase was extracted with MTBE (1 litre). The combined organics were washed
with 1 N hydrochloric acid (1 × 1 litre, 1 × 0.5 litres). To the combined acidic
washes was added a mixture of 1:1 MTBE–toluene (1.5 litres) and sodium
hydroxide (80 g) while stirring. The organics were separated when all the solids
dissolved and the aqueous was re-extracted with 1:1 toluene–MTBE (0.5 litres).
The combined organics were dried over sodium sulfate and concentrated in
vacuo. The resultant solids were slurried in heptane (1 litre) at 60 °C and then
cooled to 0 °C . After 1 h, the solids were collected by filtration and dried to give
18 (175 g, 86% yield over three steps) whose spectral properties were found to be
in accordance with those previously reported.9
Scheme 5 Manufacturing of ketone 6.
between – 10 and 0 °C. A suspension formed during the addition and after
30 min only a trace of benzoin remained by LC analysis. Water (11 litres) was
added and the resulting suspension was cooled to 5 °C. The solids containing
13 were collected by filtration and washed with water (2 litres). The solids were
suction dried for 48 h and then suspended in toluene (7 litres). p-Toluene-
sulfonic acid (20 g, 105 mmol, 0.03 equiv.) was added and the mixture was
refluxed under Dean–Stark conditions with water removal until the reaction
was complete by LC. The reaction was allowed to cool to 40 °C and ethyl
acetate (6 litres) was added followed by saturated aqueous sodium bicarbonate
(2 litres). The organics were separated and dried over sodium sulfate (250 g).
The sodium sulfate was removed by filtration and the organics were
concentrated in vacuo to dryness. The obtained solids were suspended in
tert-butyl methyl ether (2.8 litres) and heated to 55 °C while stirring for 1.5 h.
The resulting slurry was cooled to 2 °C for 2 h, and the solids were collected by
filtration and washed with tert-butyl methyl ether (1.5 litres). The solids were
dried in vacuo to provide 14 (672 g, 75% yield) whose spectral properties were
found to be in accordance with those previously reported.10
(4R,5S)-4,5-Diphenyl-1,2,3-oxathiazolidine 2,2-dioxide (15)
To a mixture of 14 (669 g, 2.44 mol) and ethyl acetate (6 litres) was added freshly
distilled formic acid-triethylamine complex (1.83 kg). The catalyst RhCl[(S,S)-
TsDPEN)Cp* (780 mg, 0.05 mol %) was added in a single portion and the
resulting mixture was allowed to stir at 20 °C for 18 h at which time LC/MS
analysis indicated consumption of 14. The mixture was added to 20% w/w citric
acid in water (5 litres) and stirred for 15 min. The phases were separated and the
organics were washed with water (3 litres). The organics were passed through a
silica gel pad (500 g) which was preequilibrated with ethyl acetate. The silica gel
pad was further eluted with ethyl acetate (2.5 litres) and the combined filtrates
were concentrated in vacuo to provide 15 (655 g, 97% yield) whose spectral
properties were found to be in accordance with those previously reported.10
Analytical data for 17
1H NMR (400 MHz, Chloroform-d) δ 8.12 (s, 1H), 7.31–7.22 (m, 8H),
7.18–7.16 (m, 2H), 6.15 (d, J =6.0 Hz, 1H), 5.19 (s, 1H), 5.15 (s, 1H), 1.38 (bs,
9H). 13C NMR (101 MHz, Chloroform-d) δ 159.96, 155.11, 138.56, 136.53,
128.47, 128.40, 128.34, 127.74, 127.1, 126.99, 79.97, 77.61, 58.82, 28.27.
N-((1R,2S)-2-Hydroxy-1,2-diphenylethyl)formamide (21)
To a 30-litre glass reactor was added formamide (18.0 kg, 400 mol, 18.9 equiv.),
(1S,2R)-2-amino-1,2-diphenylethan-1-ol (20, 4.50 kg, 21.1 mol, 1 equiv.) and
ammonium formate (270 g, 428 mmol, 0.02 equiv.). The resulting mixture was
heated to 150 °C for 2 h with agitation. The mixture was cooled to 50 °C and
the reaction was repeated at the same scale. The combined reactions were
treated with H2O (36.0 litres) and stirred at 25 °C for 2 h. The resultant solid
was isolated by filtration and the wet cake was washed with H2O (18.0 litres).
The solid was dried in vacuo at 50 °C to provide 21 (9.48 kg, 93% yield) whose
spectral properties were found to be in accordance with those previously
reported.9
tert-Butyl (4R,5S)-4,5-diphenyl-1,2,3-oxathiazolidine-3-carboxylate
2,2-dioxide (16)
To a solution of 15 (254 g, 922 mmol, 1 equiv.) in dichloromethane (1.2 litres)
was added di-tert-butyl dicarbonate (211 g, 968 mmol, 1.05 equiv.) and DMAP
(4.5 g, 37 mmol, 0.04 equiv.). The resulting mixture was allowed to stir for 1 h
at 20 °C, and then saturated aqueous sodium bicarbonate (600 ml) was added.
The mixture was stirred vigorously for 0.5 h, and the resultant phases were
allowed to separate. The organics were separated and passed through a pad of
silica gel (250 g) preequilibrated with dichloromethane. The silica gel pad was
further eluted with ethyl acetate (1.25 litres), and the combined filtrates were
concentrated in vacuo to provide 16 (334 g, 96% yield) whose spectral
properties were found to be in accordance with those previously reported.10
(1R,2R)-2-Amino-1,2-diphenylethan-1-ol (22)
To a 50-litre reactor was added CH3CN (14.0 kg) and alcohol 21 (9.35 kg,
38.8 mol 1 equiv.). The resulted mixture was cooled to 0 °C and the first
portion of SOCl2 (11.2 kg, 94.1 mol, 2.42 equiv.) was added slowly while
maintaining the temperature at o15 °C. The reaction was then stirred at 0 °C
for 30 min. The second portion of SOCl2 (21.1 kg, 177.4 mol, 4.57 equiv.) was
added slowly while maintaining the temperature at o15 °C. The reaction was
(1R,2R)-Pseudoephenamine (18) from tert-butyl (4R,5S)-4,5-
diphenyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (16)
To a cooled mixture of cesium carbonate (289 g, 889 mmol, 1 equiv.) in then stirred at 0 °C for 2 h. To a 500-litre reactor was added H2O (140 litres)
dimethylformamide (DMF; 600 ml) was added formic acid (67 ml, 1.77 mol, 2 and then cooled to 5 °C. The SOCl2 solution was then added slowly into the
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Large-scale production of fully synthetic macrolides
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reactor while maintaining the temperature at o30 °C. The suspension was
heated to 90 °C. After 12 h, the mixture was cooled to 5 °C and then aqueous
sodium hydroxide (25%, 112 kg) was added slowly to adjust to pH411. The
suspension was stirred at 15 °C for 2 h and the solid was isolated by filtration.
The wet cake was washed with H2O (19 litres) and dried at 50 °C for 18 h. The
solid was slurried in n-heptane (15.9 kg) and anhydrous ethanol (3.65 kg) at
15 °C for 18 h. The solid was isolated by filtration and the wet cake was washed
with n-heptane (13.0 kg). The solid was dried in vacuo at 50 °C to provide 22
(7.2 kg, 85% yield, 100% ee) whose spectral properties were found to be in
accordance with those previously reported.9
(920 ml). The organics were concentrated in vacuo while azeotropically drying
with toluene (2× 575 ml). The residue was slurried in a mixture of toluene
(581 ml) and hexanes (290 ml) at 20 °C for 1 h. The suspension was filtered
and the wet cake was washed with toluene (290 ml) and hexanes (145 ml). The
solid was dried under a stream of nitrogen to provide 25 (178 g, 95% yield)
whose spectral properties were found to be in accordance with those previously
reported.13
2-Amino-N-((1R,2R)-2-hydroxy-1,2-diphenylethyl)-N-
methylacetamide (4)
To a solution of 25 (178 g, 0.478 mol) in dichloromethane (558 ml) cooled to
10 °C, trifluoroacetic acid (291 ml, 3.82 mol, 8 equiv.) was added slowly while
maintaining the temperature at o15 °C. After 1 h, the reaction was warmed to
20 °C and stirred for 16 h. Upon reaction completion, the reaction mixture was
concentrated in vacuo with toluene (3 × 581 ml) to yield a yellow oily residue
(385 g). The residue was dissolved in dichloromethane (2.61 litres) and cooled
to 10 °C. The solution was stirred vigorously while 3 M aq. NaOH was added
slowly at a temperature of ⩽ 15 °C until the solution reached a pH of ~ 13–14.
Stirring was discontinued and the layers were separated. The aqueous layer was
back extracted with dichloromethane (2× 372 ml). The combined organic
layers were washed with H2O (2 × 558 ml) and then concentrated in vacuo to a
total volume of ~ 1 litre. Potassium carbonate (160 g) was added and the
suspension was stirred for 0.5 h. The solids were removed by filtration through
Celite and the filtrate was concentrated in vacuo with toluene (3× 581 ml). The
formed solids were re-slurried in toluene (744 ml) at 23 °C for 6 h and then 0 °C
for 2 h. The product was isolated by filtration, washed with toluene (127 ml) and
dried in vacuo to provide 4 (130 g, 94% yield) in 98% HPLC purity whose
spectral properties were found to be in accordance with those previously
N3-((1R,2R)-2-Hydroxy-1,2-diphenylethyl)formamide (23)
To a 50-litre reactor was added acetic anhydride (Ac2O, 6.7 kg, 65.5 mol, 2.00
equiv.) and formic acid (3.63 kg, 78.6 mol, 2.4 equiv.). The mixture was
warmed to 60 °C, stirred for 1 h and then cooled to 10 °C. To a 300-litre
reactor was added 2-methyltetrahydrofuran (2-MeTHF, 91 kg) and amino
alcohol 22 (6.98 kg, 32.7 mol, 1 equiv.). The suspension was cooled to − 40 °C.
The solution of anhydride was added slowly into the suspension of 22 while
maintaining the temperature at o − 30 °C. The resultant solution was stirred at
− 40 °C for 1 h and then warmed to 25 °C. After 2 h, the mixture was cooled to
0 °C and aqueous sodium hydroxide (20%, 84.0 kg) was added slowly into the
mixture while maintaining the temperature at o15 °C. The mixture was then
stirred at 25 °C for 2 h. Stirring was discontinued and the layers were allowed to
separate. After 1 h, the aqueous was removed and the organic phase was washed
with 10% aqueous sodium chloride (63.0 kg). The organic phase was
concentrated in vacuo to a total volume of 21 litres. 2-MeTHF (18.2 kg) was
added into the reactor and the mixture was concentrated in vacuo to about
21 litres, and this process was repeated once more. n-Heptane (28.7 kg) was
added slowly with stirring and the resultant suspension was stirred at 10 °C for reported.13
2 h. The solid was isolated by filtration and the wet cake was washed with n-
heptane (9.8 kg). The solid was dried in vacuo at 50 °C to provide 23 (7.6 kg,
(3R,4S,6R)-4-(Dimethylamino)-6-methyltetrahydro-2H-pyran-2,3-
diol, hydrochloric acid salt (26)
95% yield) whose spectral properties were found to be in accordance with those
previously reported.9
Erythromycin (1, 59.5 kg, 81.1 mol) and 3 N hydrochloric acid (125 kg) were
added to a 500-litre reactor. The mixture was heated to 85 °C and stirred for
6 h. Toluene (41 kg) was added to the mixture at 85 °C. The mixture was
cooled to 25 °C and dichloromethane (250 kg) was added. The mixture was
stirred for 1 h and the layers were then allowed to settle for 1 h. The organic
layer was removed and the aqueous layer was washed with dichloromethane
(3 × 44 kg). The aqueous solution was concentrated in vacuo at o70 °C.
2-Propanol (141 kg) was added to the residue and the mixture was concentrated
in vacuo at o55 °C (repeated 2 × ) to yield an off-white solid. Dichloromethane
(154 kg) was added to the residue and the mixture was concentrated in vacuo at
o40 °C. The resultant solid was slurried in dichloromethane (78 kg) at 15 °C for
12 h. The suspension was filtered and the wet cake was washed with
dichloromethane (24 kg) and dried in vacuo at 40 °C to provide 26 (11.26 kg
solid, 10.4 kg corrected, 60% yield) whose spectral properties were found to be in
accordance with those previously reported.15
(1R,2R)-2-(Methylamino)-1,2-diphenylethan-1-ol (18)
To a 200-litre reactor was added toluene (31.0 kg), THF (13.0 kg) and 23
(7.28 kg, 30.2 mol, 1 equiv.). The mixture was cooled to 0 °C and lithium
aluminum hydride (1.0 M in THF, 48.0 kg, 53.5 mol, 1.77 equiv.) was added
slowly into the mixture while maintaining the temperature at o15 °C. The
mixture was stirred at 0 °C for 0.5 h and then warmed at 50 °C for 12 h. The
mixture was cooled to 0 °C and H2O (2.2 kg) was added slowly while
maintaining the temperature o20 °C. Aqueous sodium hydroxide (8%,
4.6 kg) was added followed by H2O (6.6 litres). The resultant suspension was
stirred at 20 °C for 1 h and then filtered. The wet cake was washed with THF
(13.0 kg). The combined filtrate was concentrated in vacuo to a volume
22 litres. THF (20 kg) was added and the mixture was concentrated in vacuo to
about 22 litres. n-Heptane (30.0 kg) was added slowly and the suspension was
stirred at 15 °C for 2 h. The resultant solid was isolated by filtration and the wet
cake was washed with n-heptane (10.0 kg). The solid was dried in vacuo at 50 °C
to provide 18 (6.28 kg, 83% yield, 99% HPLC purity) whose spectral properties
were found to be in accordance with those previously reported.9
(3R,4S,6R)-4-(Dimethylamino)-6-methyltetrahydro-2H-pyran-2,3-
diyl dibenzoate (27)
In a 500-litre reactor, diol 26 (9.00 kg, 42.5 mol, 1 equiv.) was suspended in
dichloromethane (96 kg). The mixture was cooled to 0 °C and triethylamine
(17.1 kg, 169 mol, 4 equiv.) was added slowly while maintaining the tempera-
ture at o5 °C. DMAP (0.60 kg, 4.91 mol, 0.12 equiv.) was added. A solution of
benzoic anhydride (23.4 kg, 103 mol, 2.42 equiv.) in dichloromethane (24 kg)
was then added slowly over 20 h while maintaining the temperature at o5 °C.
After 0.5 h, the mixture was warmed to 25 °C and stirred for 16 h. Upon
reaction completion, the mixture was cooled to 15 °C and quenched with
saturated aqueous NaHCO3 (98 kg) while maintaining the temperature at
o30 °C. The layers were separated and the organic was washed with saturated
aqueous sodium bicarbonate (48 kg) and H2O (46 kg). The organics were
concentrated in vacuo at o40 °C. Toluene (78 kg) was added to the residue and
tert-Butyl (2-(((1R,2R)-2-hydroxy-1,2-diphenylethyl)(methyl)
amino)-2-oxoethyl)carbamate (25)
N-Boc-glycine (24, 114 g, 0.651 mol, 1.28 equiv.) was dissolved in dichlor-
omethane (920 ml) and cooled to 0 °C. Triethylamine (91.4 ml, 0.655 mol, 1.3
equiv.) was then added dropwise while maintaining the temperature at o3 °C
(5 min addition time). The mixture was stirred for 0.5 h. Pivaloyl chloride
(74.4 ml, 0.605 mol, 1.20 equiv.) was then added dropwise while maintaining
the temperature at o3 °C. The resultant white suspension was stirred for
40 min and then a second portion of triethylamine (91.4 ml, 0.655 mol, 1.3
equiv.) was added dropwise while maintaining the temperature at o5 °C.
Finely powdered (1R,2R)-pseudoephenamine (18, 115 g, 0.506 mol, 1 equiv.) the mixture was concentrated in vacuo at o60 °C. The mixture was cooled to
15 °C and 0.5 N hydrochloric acid (109 kg) was added to the residue. The
was added in portions over 20 min while maintaining the temperature at o5 °C.
The reaction mixture was allowed to stir at 0 °C for 1 h. The mixture was then aqueous mixture was washed with MTBE (40 kg) and then adjusted to a pH of
washed with H2O (920 ml) and saturated aqueous sodium bicarbonate 9 with solid potassium carbonate (5.5 kg). The aqueous mixture was extracted
The Journal of Antibiotics

Large-scale production of fully synthetic macrolides
PC Hogan et al
7
with MTBE (67 kg) and the organic layer was concentrated in vacuo at o45 °C. mixture was allowed to warm to 23 °C and the phases were separated. A
Ethyl acetate (18 litres), heptane (9 litres) and silica gel (5.1 kg) were added and solution of 2 N sodium hydroxide (28 kg) was added to the organic phase and
the resultant mixture was stirred at 25 °C for 2 h. The mixture was filtered the mixture was stirred for 6 h. The phases were then separated and the organic
through a silica gel pad (9 kg) and the pad was further eluted with a mixture of phase was washed with water (3× 20 litres). The organic layer was concentrated
in vacuo to provide crude 31 (6.7 kg). This procedure was repeated on a second
batch at a similar scale (tert-butyl propionate (4.5 kg, 34.6 mol)) using the same
procedure to yield crude product (7.0 kg) whose spectral properties were found
to be in accordance with those previously reported.16 This material was used
directly in the next step.
ethyl acetate (68 litres) and heptane (23 litres). The combined filtrates were
concentrated in vacuo to about ~ 30 litres at o50 °C to provide 27 as a solution
(25.4 kg solution, Assay: 53.3%, 90.5% yield) whose spectral properties were
found to be in accordance with those previously reported.15
(3R,4S,6R)-4-(Dimethylamino)-6-methyl-2-(pyrimidin-2-ylthio)
tetrahydro-2H-pyran-3-yl benzoate, oxalate salt (oxalate salt of 5)
A solution of 27 (25.2 kg, 53.3% assay, 35.0 mol, 1 equiv.) was charged into a
200-litre reactor. The mixture was concentrated in vacuo at o50 °C. Toluene
(47 kg) was added and the mixture was concentrated in vacuo at o55 °C. The
mixture was cooled to 20 °C and dichloromethane (74 kg) was charged to
the residue. Pyrimidine-2-thiol (4.6 kg, 41.0 mol, 1.17 equiv.) was added and the
mixture was cooled to −5 °C. Trimethylsilyl trifluoromethanesulfonate (23.2 kg,
104 mol, 3 equiv.) was added slowly while maintaining the temperature at o0 °
C. The mixture was stirred for 0.5 h and then allowed to slowly warm to 25 °C.
The mixture was stirred for 16 h. Upon reaction completion, the mixture was
cooled to 0 °C and added slowly to saturated aqueous sodium bicarbonate
(146 kg) while maintaining the temperature at o5 °C. Dichloromethane (74 kg)
was added followed by saturated aqueous potassium carbonate (35 kg). The
mixture was heated to 25 °C and stirred for 0.5 h (aqueous pH =9). The layers
were separated and the organic layer was washed with saturated aqueous sodium
6-Ethyl-2,2,5-trimethyl-4H-1,3-dioxin-4-one (32)
A mixture of the combined lots of crude 31 (13.5 kg, 73.5 mol, 1 equiv.),
acetone (8.50 kg, 146 mol) and acetic anhydride (22.5 k g, 220 mol, 3 equiv.)
was cooled to 0 °C. A solution of concentrated sulfuric acid (7.40 kg, 74.0 mol,
1.01 equiv.) was added slowly while maintaining the temperature at ⩽ 15 °C.
The reaction was then stirred at 23 °C for 4 h. Upon reaction completion, the
reaction mixture was added into cooled water (15.1 litres) at ⩽ 10 °C. A solution
of 4 N sodium hydroxide was added while maintaining the temperature at ⩽ 10 °
C until pH 7–8. The mixture was stirred for 0.5 h at 10 °C. The mixture was
then extracted with MTBE (2 × 67 kg) and the combined organic layers were
washed with H2O (25 litres). The organic phase was concentrated in vacuo. The
residue was then purified by vacuum distillation (100 °C, −0.09 MPa) to
provide 32 (5.74 kg, 57% 2-step yield, 99% HPLC purity) whose spectral
properties were found to be in accordance with those previously reported.16
bicarbonate (58 kg). The organic layer was concentrated in vacuo at o40 °C. The (Z)-((4-Ethylidene-2,2,5-trimethyl-4H-1,3-dioxin-6-yl)oxy)
mixture was cooled to 15 °C and dissolved in aqueous citric acid (136 kg, 4.63%
w/w). The aqueous mixture was washed with MTBE (2 × 26 kg) and the aqueous
layer was made basic with potassium carbonate (9.7 kg) to a pH of 8.4. The
product was extracted with MTBE (81 kg) and the organic layer was washed with
H2O (41 kg). The organics were concentrated in vacuo at o45 °C. Toluene
(47 kg) was added to the residue and the mixture was concentrated in vacuo at
o60 °C. Toluene (11 kg) was added to the residue and the mixture was heated to
25 °C and stirred for 0.5 h. The toluene solution was filtered through a silica pad
(25.9 kg, preequilibrated with hexanes). The silica pad was washed with a mixture
of 20% acetone in hexanes containing 1% triethylamine (323 kg). Sufficiently
pure fractions were combined and concentrated in vacuo at o45 °C. Toluene
(47 kg) was added to the residue and the mixture was concentrated at o60 °C.
The mixture was cooled to 25 °C and acetone (16 kg) was added followed by
anhydrous oxalic acid (2.70 kg, 30.0 mol). The suspension was stirred at 25 °C
for 2 h. Toluene (24 kg) was added slowly to the mixture and then cooled to 10 °
C. After 2 h, the suspension was filtered and the wet cake was washed with
toluene (12 kg). The yellow solid was dried in vacuo at ⩽45 °C to provide the
oxalate salt of 5 (11.6 kg, 71.4% yield) in 99.8 % HPLC purity (sum of anomers).
trimethylsilane (7)
To a cooled suspension of triethylamine hydrochloride (0.02 eq, 4.41 g) in THF
(1620 ml) was added diiisopropylamine (270 ml) and n-BuLi (2.5M, 784 ml)
keeping the temperature between −10 and − 20 °C. The mixture was cooled in
a dry ice acetone bath and 32 (d = 1.04, 264 ml) was added maintaining a
temperature between − 65 and − 70 °C, The resultant orange mixture was
stirred for 1 h at −73 °C and chlorotrimethylsilane ( 244 ml) was added
keeping the temperature at o − 68 °C. After 2 h, the reaction was allowed to
warm freely to 20 °C over 1 h and then concentrated at 35 °C (bath
temperature) at a pressure of 30 mbar. Heptane (1 litre) was added and the
mixture was concentrated in vacuo. To the resulting suspension was added
heptane (2 litres) and the solids were removed by filtration through a small pad
of Celite while under a blanket of nitrogen. The pad was further eluted with
heptane (1 litre). Concentration of this solution and distillation of the residue
as previously reported provided the silyl enol ether 7 (330 g) containing
~ 10 mol% 32 (79% yield corrected) by 1H NMR analysis and whose spectral
properties were found to be in accordance with those previously reported. 15
(R)-2-Methylpent-1-en-3-ol (35)
Analytical data for the oxalate salt of 5
To a 200-litre vessel was added (1R,2S)-1-cyclohexyl-2-morpholino-2-pheny-
lethan-1-ol (34, 360 g, 1.25 mol%) and n-hexane (9.5 kg) under an atmosphere
of nitrogen. A solution of diethylzinc (1.0 M in hexanes, 100 litres, 100 mol, 2
equiv.) was added to the mixture while maintaining the temperature at ⩽ 15 °C.
The mixture was heated to 35 °C and stirred for 1 h. The mixture was cooled to
15 °C and a solution of methacrolein (33, 3.50 kg, 50.0 mol, 1 equiv., freshly
distilled) in hexane (21.0 kg) was added slowly over 2 h while maintaining the
temperature at ⩽ 15 °C. The mixture was stirred for 16 h at 15 °C. Upon
reaction completion, the reaction mixture was quenched slowly into a solution
of 20% aqueous ammonium chloride (120 kg). The mixture was filtered and
the solid was washed with hexane (24.0 kg). The combined filtrates were
separated and the organic layer was washed with aqueous sodium chloride
(15%, 2 × 60.0 kg). The organics were concentrated in vacuo at o10 °C. The
residue was purified by vacuum distillation (65–68 °C at ~ 40 Torr) to provide
35 as a colorless liquid (3.5 kg, 70% yield) whose spectral properties were found
to be in accordance with those previously reported.18
1H NMR (400 MHz, DMSO-d6) δ 8.64 (d, J = 5.2 Hz, 2H), 7.88–7.86 (m, 2H),
7.65–7.60 (m, 1H), 7.46 (dd, J = 7.6 Hz, 2H), 7.25 (dd, J = 4.8 Hz, 1H), 5.88
(d, J = 9.6 Hz, 1H), 5.31 (t, J = 10.0 Hz, 1H), 3.88 (dtt, J = 13.3, 7.1, 3.5 Hz,
1H), 3.77–3.71 (m, 1H), 2.55 (s, 6H), 2.11 (bd, J = 12.0 Hz, 1H), 1.67
(q, J =12.1 Hz, 1H), 1.23 (d, J = 6.1 Hz, 3H). 13C NMR (101 MHz, Metha-
nol-d4) δ 170.17, 167.40, 165.88, 159.10, 159.03, 134.93, 131.08, 130.18, 129.63,
119.24, 84.14, 74.25, 69.14, 66.11, 40.56, 31.28, 21.28, 21.24.
tert-Butyl 2-methyl-3-oxopentanoate (31)
Hexamethyldisilazane (5.08 kg, 31.5 mol, 1.02 equiv.) was dissolved in THF
(11 kg) and cooled to −20 °C. A solution of n-BuLi (2.5 M, hexanes, 12.6 litres,
31.6 mol, 1.03 equiv.) was added slowly while maintaining the temperature at
o − 5 °C. In another vessel, diisopropylamine (3.20 kg, 31.6 mol, 1.03 equiv.)
was dissolved in THF (22 kg) and then cooled to −65 °C. n-BuLi (2.5 M,
hexanes, 12.6 litres, 31.6 mol, 1.03 equiv.) was added slowly followed by slow
addition of tert-butyl propionate (29, 4.00 kg, 30.7 mol, 1 equiv.) at ⩽− 65 °C.
The solution of LiHMDS in THF was then added slowly at ⩽ − 65 °C followed
(R)-tert-Butyl((2-methylpent-1-en-3-yl)oxy)diphenylsilane (36)
by a solution of phenyl propionate (30, 4.16 kg, 27.7 mol, 0.90 equiv.) in THF To a 50-litre vessel was charged 35 (2.40 kg, 24.0 mol, 1 equiv.) and imidazole
(6 kg) at ⩽− 65 °C. The reaction was stirred at ⩽ −65 °C for 1 h. Upon reaction (3.30 kg, 48.0 mol, 2 equiv.) in DMF (24 litres). TBDPSCl (7.90 kg, 28.8 mol,
completion, 20% aqueous ammonium chloride (24 kg) was added slowly. The 1.2 equiv.) was added to the mixture over 0.5 h while maintaining the
The Journal of Antibiotics

Large-scale production of fully synthetic macrolides
PC Hogan et al
8
temperature at ⩽ 15 °C. The reaction was stirred for 20 h at 23 °C. The reaction
was added to a mixture of H2O (72 litres) and heptane (66 litres). The aqueous
layer was removed and the organic phase was washed with H2O (72 litres). The
organics were concentrated in vacuo at ⩽ 40 °C. The crude product was filtered
through a pad of silica gel (12.0 kg) eluting with heptane to provide 36 as a
colorless oil (7.0 kg, 86.4% yield) whose spectral properties were found to be in
accordance with those previously reported.18
1
2
Bryskier, A. & Bergogne-Berezin, E. in Antimicrobial Agents:Antibacterials and Anti-
fungals (ed. Bryskier, A.) 475-526 (ASM Press, Washington DC, USA, 1982).
Liang, J. H. & Han, X. Structure-activity relationships and mechanisms of action of
macrolide derived from erythromycin as antibacterial agents. Curr. Top. Med. Chem. 13,
3131–3164 (2013).
3
4
Fernandes, P. B. Methods for treating gastrointestinal diseases. WO patent 2010-
/048599 (2010).
Putnam, S. D., Castanheira, M., Moet, G. J., Farrell, D. J. & Jones, R. N. CEM-101, A.
Novel Fluoroketolide Antimicrobial activity against a diverse collection of gram-positive
and Gram-negative bacteria. Diagn. Microbiol. Infect. Dis. 66, 393–401 (2010).
Morimoto, S., Takahashi, Y., Watanabe, Y. & Omura, S. Chemical modification of
erythromycins. I. Synthesis and antibacterial activity of 6-O-methylerythromycins A. J.
Antibiot. 37, 187–189 (1984).
Slobodan, D. et al. Erythromycin series. Part 13. Synthesis and structure elucidation of
10-dihydro-10-deoxo-11-methyl-11-azaerythromycin A. J. Chem. Res. Synop. 1988,
152–153 (1988).
Lynch, J. P. & Zhanel, G. G. Streptococcus pneumoniae: does antimicrobial resistance
matter? Semin. Respir. Crit. Care Med. 30, 210–238 (2009).
Seiple, I. B. et al. A platform for the discovery of new macrolide antibiotics. Nature 533,
338–345 (2016).
(R)-3-((tert-Butyldiphenylsilyl)oxy)pentan-2-one (6)
5
6
To a 300-litre vessel was charged 36 (6.5 kg, 19.2 mol, 1 equiv.), 2,6-lutidine
(4.1 Kg, 38.4 mol, 2 equiv.), THF (3.5 litres), and water (1.5 liters) and the
resultant mixture was cooled to 15 °C. Potassium osmate dihydrate (0.11 kg,
0.29 mol) and NaIO4 (16.4 kg, 76.8 mol, 4 equiv.) were added and the mixture
was heated to 25 °C and stirred for 20 h. Upon reaction completion, the mixture
was cooled 5 °C. An aqueous solution of sodium thiosulfate (18%, 142 kg) was
added to the mixture over 2 h. Upon complete addition, the mixture was stirred
at 5 °C for 1 h. Heptane (93.0 kg) was added and the resultant suspension was
filtered. The solid was washed with hexane (10.0 kg). The organic layer was
separated from the filtrate and washed with a solution sodium thiosulfate (4%,
2 ×73 kg) and aqueous copper (II) sulfate (5%, 2 ×73 kg). The organics were
concentrated in vacuo at ⩽40 °C. The crude product was purified by filtration
through a pad of silica gel (35.0 kg) eluting with 10% ethyl acetate in heptane to
provide 6 as a pale yellow oil (5.25 kg, 80.4% yield) in 98% HPLC purity and
99% chiral HPLC purity whose spectral properties were found to be in
accordance with those previously reported.18
7
8
9
Morales, M. R., Mellem, K. T. & Myers, A. G. Pseudoephenamine: a practical chiral
auxiliary for asymmetric synthesis. Ang. Chem. Int. Ed. 51, 4568–4571 (2012).
10 Han, J., Kang, S. & Lee, H.-K. Dynamic kinetic resolution in the stereoselective
synthesis of 4,5-diaryl cyclic sulfamidates by using chiral rhodium-catalyzed asym-
metric transfer hydrogenation. Chem. Commun. (Camb.) 47, 4004–4006 (2011).
11 McLaughlin, M. et al. Practical asymmetric synthesis of a chiral piperazinone derivative.
Org. Proc. Res. Dev. 17, 1052–1060 (2013).
12 Weijlard, J., Pfister, K. III, Swanezy, E. F., Robinson, C. A. & Tishler, M. Preparation of
the stereoisomeric α, β-diphenyl-β-hydroxyethylamines. J. Am. Chem. Soc. 73,
1216–1218 (1951).
13 Seiple, I. B., Mercer, J. A. M., Sussman, R. J., Zhang, Z.
& Myers, A. G.
Stereocontrolled synthesis of syn-β-hydroxy-α-amino acids by direct aldolization of
pseudoephenamine glycinamide. Ang. Chem. Int. Ed. 53, 4642–4644 (2014).
14 Woodward, R. B. et al. Asymmetric total synthesis of erythromycin. 3. Total synthesis of
erythromycin. J. Am. Chem. Soc. 103, 3215–3217 (1981).
15 Zhang, Z. A Platform for the Discovery of New Macrolide Antibiotics. (PhD thesis,
Harvard Univ., 2016).
DEDICATION
This manuscript is dedicated with respect and admiration to Professor
KC Nicolaou in recognition of his manifold contributions to chemistry.
16 Zhang, Z., Kitamura, Y. & Myers, A. G. An efficient directed claisen reaction allows for rapid
construction of 5,6-disubstituted 1,3-dioxin-4-ones. Synthesis 47, 2709–2712 (2015).
17 Gupta, L., Hoepker, A. C., Sing, K. J. & Collum, D. B. Lithium diisopropylamide-
mediated ortholithiations: lithium chloride catalysis. J. Org. Chem. 74,
2231–2233 (2009).
18 Seiple, I. B., Hog, D. T. & Myers, A. G. Practical protocols for the preparation of highly
enantioenriched silyl ethers of (R)-3-hydroxypentan-2-one, building blocks for the
synthesis of macrolide antibiotics. Synlett 27, 57–60 (2016).
CONFLICT OF INTEREST
The authors declare no conflict of interest.
ACKNOWLEDGEMENTS
We thank Dr Yoshi Ichikawa and Dr Ziyang Zhang for helpful discussions
during the preparation of this manuscript.
Supplementary Information accompanies the paper on The Journal of Antibiotics website (http://www.nature.com/ja)
The Journal of Antibiotics