New, efficient, and high-yielding asymmetric synthesis of (4S,5S)-cytoxazone

Article abstract of DOI:10.1080/00397911.2011.563450

(Chemical Equation Presented) A new approach for the asymmetric synthesis of (4S,5S)-cytoxazone 1 in five steps and in 48% overall yield starting from commercially available (R)-epichlorohydrin has been described. The key step include stereoselective 1,2-

Full text of DOI:10.1080/00397911.2011.563450

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New, Efficient, and High-Yielding
Asymmetric Synthesis of (4S,5S)-
Cytoxazone
Kollapudi Chandra Babu a b , Rapolu Naveen Reddy a , Salluri
Yellamanda Rao a , Palnati Venkateshwarlu a & Gutta Madhusudhan a
a Department of Research and Development, Inogent Laboratories
Private Limited , Hyderabad , India
b Centre for Pharmaceutical Sciences, Institute of Science and
Technology, Jawaharlal Nehru Technological University , Hyderabad ,
India
Accepted author version posted online: 31 Oct 2011.Published
online: 29 May 2012.
To cite this article: Kollapudi Chandra Babu , Rapolu Naveen Reddy , Salluri Yellamanda Rao , Palnati
Venkateshwarlu & Gutta Madhusudhan (2012) New, Efficient, and High-Yielding Asymmetric Synthesis
of (4S,5S)-Cytoxazone, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 42:17, 2624-2631, DOI: 10.1080/00397911.2011.563450
To link to this article: http://dx.doi.org/10.1080/00397911.2011.563450
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Synthetic Communications1, 42: 2624–2631, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.563450
NEW, EFFICIENT, AND HIGH-YIELDING ASYMMETRIC
SYNTHESIS OF (4S,5S)-CYTOXAZONE
Kollapudi Chandra Babu,1,2 Rapolu Naveen Reddy,1
Salluri Yellamanda Rao,1 Palnati Venkateshwarlu,1 and
Gutta Madhusudhan1
1Department of Research and Development, Inogent Laboratories Private
Limited, Hyderabad, India
2Centre for Pharmaceutical Sciences, Institute of Science and Technology,
Jawaharlal Nehru Technological University, Hyderabad, India
GRAPHICAL ABSTRACT
Abstract A new approach for the asymmetric synthesis of (4S,5S)-cytoxazone 1 in five
steps and in 48% overall yield starting from commercially available (R)-epichlorohydrin
has been described. The key step include stereoselective 1,2-addition of p-methoxyphenyl
magnesium bromide (p-OMePhMgBr) to chiral N-sulfinimine derived from
(R)-glyceraldehyde acetonide and (S)-t-BSA, which gave corresponding sulfinamide 2 with
high diastereoselectivity. Deprotection of the t-butylsulfonyl group and 1,3-dimethyl acetal
in a single step followed by N-Boc protection and subsequent carbonylation yields the tar-
geted (4S,5S)-cytoxazone 1.
Keywords Chiral N-sulfinimine; (R)-glyceraldehyde acetonide; (4R5R)-cytoxazone;
(4S5S)-cytoxazone; stereoselective 1,2-addition
Received December 28, 2010.
Address correspondence to Gutta Madhusudhan, Department of Research and Development,
Inogent Laboratories, 28 A, IDA, Nacharam, Hyderabad 500 076, Andhra Pradesh, India. E-mail:
madhusudhan.gutta@inogent.com; madhusudhan.gutta@yahoo.com
2624

ASYMMETRIC SYNTHESIS OF (4S,5S)-CYTOXAZONE
2625
INTRODUCTION
(4R,5R)-Cytoxazone 1 is a microbial metabolite[1] isolated from Streptomyces
sp.,[2] which has been identified as a selective modulator of Th2 cytokine secretion.
Inhibitors of Th2-dependent cytokine production have potential as potent che-
motherapeutic agents in the field of immunotherapy. (4R,5R)-Cytoxazone 1 is differ-
ent from known immunomodulators such as FK 506 and rapamycin with respect to
structure and biological activity. As such, 1 should be a useful tool for understanding
signalling pathways in Th2 cells. Because of its potent biological activity and rela-
tively simple structure, the development of efficient asymmetric routes to cytoxazone
and its stereoisomers has been the subject of intense synthetic interest. A variety of
synthetic routes to 1 have been previously reported in 10% to 51% overall yield,
including chemoenzymatic resolution,[3] imino 1,2-Wittig rearrangement,[4] addition
of Grignard reagents to a protected imine,[5] Sharpless asymmetric dihydroxylation
and regio- and stereoselective introduction of azide,[6,7] asymmetric aminohydroxyla-
tion[8] and asymmetric aldol reactions.[9] Most of these reported methods are for the
synthesis of (4R,5R)-1 only but are limited for getting (4S,5S)-1 directly.[10] Naito
et al. synthesized (4S,5S)-1 staring from (R)-a-hydroxy oxime ether in five steps
and 9% overall yield by diastereoselective imino 1,2-Wittig rearrangement.[10]
RESULTS AND DISCUSSION
Herein we report the synthesis of (4S,5S)-1 starting from (R)-glyceraldehyde
acetonide. We have previously demonstrated stereoselective addition of phenyl-
magnesium bromide (PhMgBr) to N-sulfinimine derived from (R)-glyceraldehyde
acetonide and (S)-t-BSA with high diastereoselectivity followed by deprotection of
the t-butylsulfonyl group and 1,3-dimethyl acetal in a single step, resulting in the
corresponding syn-b-amino alcohol. The amine functionality of obtained b-amino-
alcohol was protected as N-Boc derivative and finally proceeded to 2-oxazolidinone
ring formation.[11] It was envisaged that this methodology would allow an efficient
and stereoselective asymmetric synthesis of (4S,5S)-cytoxazone 1 via synthetic
elaboration of the N-sulfinimine 3 derived from (R)-glyceraldehyde acetonide and
(S)-t-BSA by the stereoselective addition of p-methoxyphenylmagnesium bromide
(p-OMePhMgBr) (Fig. 1).
In this context, (R)-glyceraldehyde acetonide is regarded as a common starting
material, which has previously been synthesized by us in four steps and in 31% over-
all yield starting from commercially available (R)-epichlorohydrin.[11] Previously,
(R)-glyceraldehyde acetonide was also elaborated to (S,E)-N-(((S)-2,2-dimethyl-1,3-
dioxolan-4-yl)methylene)-2-methylpropane-2-sulfinamide 3 by the reaction of
(R)-glyceraldehyde acetonide with (S)-t-butylsulfinamide [(S)-t-BSA] using CuSO4
in dichloromethane at room temperature with 98.94% de (Scheme 1).[11]
The chiral a-hydroxy-N-sulfinimines have recently received much attention as
important precursors and intermediates for the preparation of a wide variety of
natural products and drugs.[12] Furthermore, they can be easily converted into chiral
b-amino alcohols and 2-oxazolidinones. Therefore, development of methodologies
for the stereoselective synthesis of chiral 3-amino-1,2-propanediol followed by
carbonylation to 2-oxazolidinones is of considerable interest.[8,13]

2626
K. C. BABU ET AL.
Figure 1. Retrosynthetic analysis for (4S,5S)-1.
1,2-Addition of phenylmagnesium bromide to benzyl imine derivative of (S)-4
is reported in the literature.[5] Chiral a-hydroxy-N-sulfinimine 3 on treatment
with p-OMePhMgBr in Et2O at ꢀ78 ꢁC gave the (S)-N-((S)-((S)-2,2-dimethyl-1,3-
dioxolan-4-yl)(p-methoxyphenyl)methyl)-2-methylpropane-2-sulfinamide 2 with 87%
yield. It is apparent that 1,2-addition of p-OMePhMgBr to chiral sulfinimine 3
proceeds via transition state 3a (Fig. 2).[14]
When tetrahydrofuran (THF), CH2Cl2, and toluene were used as the solvent,
no increased in yield was observed (Table 1, entries 2, 3, and 4). Deprotection of
the t-butylsulfonyl group and 1,3-dimethyl acetal in compound 2 was performed
in a single step in acidic media (MeOH ꢂ HCl) to give the corresponding syn-b-
aminoalcohol 5. The amine functionality in 5 was protected as N-Boc derivative 6.
The next step in the sequence is the formation of the 2-oxazolidinone. The N-Boc
protective group was advantageously utilized for the formation of 2-oxazolidinone
ring, thereby avoiding the protection and deprotection of primary hydroxyl group.
Scheme 1. Synthesis of (R)-glyceraldehyde acetonide 4 and (S,E)-N-(((S)-2,2-dimethyl-1,3-dioxolan-4-
yl)methylene)-2-methylpropane-2-sulfinamide 3 staring from (R)-epichlorohydrin.

ASYMMETRIC SYNTHESIS OF (4S,5S)-CYTOXAZONE
2627
Figure 2. Transition state 3a.
Table 1. 1,2-Addition of p-OMePhMgBr to chiral a-hydroxy-N-sulfinimine 3
Entry
Solvent
Temperature (ꢁC)
Time (h)
Yielda (%)
1
2
3
4
Et2O
THF
ꢀ78
ꢀ78
ꢀ78
ꢀ78
5–6
15
87 (0)
25 (42)
35 (50)
17 (60)
Toluene
CH2Cl2
15
15
aYields in parentheses are for recovered starting materials.
Thus, compound 6 on treatment with NaH in THF cyclized regioselectively to
targeted (4S,5S)-cytoxazone 1. The entire strategy is outlined in Scheme 2.
(4S,5S)-Cytoxazone 1 has been confirmed to exist in threo configuration by
1
characteristic H4 and H5 signals that appear in H NMR spectra and was in agree-
ment with reported values.[10] Because the absolute stereochemistry of (R)-4 and
t-BSA were known, the identity of the stereocenters of the 1 has been elucidated
and confirmed to be (4S,5S).
Scheme 2. Synthesis of (4S,5S)-1.

2628
K. C. BABU ET AL.
CONCLUSION
As a conclusion, an efficient method has been developed for the preparation
of (4S,5S)-1 in five steps and in 48% overall yield starting from (R)-glyceraldehyde
acetonide. The key step includes stereoselective 1,2-addition of p-methoxyphenyl
magnesium bromide (p-OMePhMgBr) to chiral N-sulfinimine derived from
(R)-glyceraldehyde acetonide and (S)-t-BSA. The synthetic strategy detailed herein
is equally applicable to the synthesis of the (4R,5R)-, (4R,5S)-, and (4S,5R)-
stereoisomers of cytoxazone using the diastereoselective 1,2-addition of p-methoxy-
phenyl magnesium bromide (p-OMePhMgBr), and the application of this strategy to
a variety of related natural products is currently under way in our laboratories.
EXPERIMENTAL
Melting points were determined on a Buchi 540 melting-point apparatus and are
uncorrected. Furier transform–infrared (FT-IR) spectra were recorded as KBr pellet
on a Nicolet 380 FT-IR instrument Thermo Electron Corporation Spectrum One),
and 1H and 13C NMR (proton decoupled) spectra were recorded on a Varian
400-MHz spectrometer using dimethylsulfoxide (DMSO-d6), CDCl3 as solvent, and
tetramethylsilane (TMS) as internal standard. Mass spectra were recorded on an Agi-
lent triple quadrupole mass spectrometer equipped with turboion spray interface at
375 ꢁC. All the organic extracts were dried over sodium sulfate after workup. The
dry reactions were carried out under a nitrogen atmosphere with magnetic=mechanical
stirring. Unless otherwise mentioned, all the solvents and reagents used were of LR
grade. Thin-layer chromatograpy (TLC) was performed on precoated silica-gel plates,
which were visualized using ultraviolet (UV) light and sulfuric acid=ethanol (5:95)
charring. Flash column chromatography was carried out on silica gel (230–400 mesh)
unless otherwise stated.
(S)-N-((S)-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)(p-methoxyphenyl)
methyl)-2-methyl Propane-2-sulfinamide (2)
A solution of p-methoxyphenylmagnesium bromide (186.2 mL, 0.257 mol,
3.0 M solution in Et2O) was added dropwise to a solution of chiral N-sulfinimine
3 (50.0 g, 0.214 mol) in Et2O (200 mL) over a period of 30 min at ꢀ78 ꢁC under an
argon atmosphere. After being stirred for 5 h at ꢀ78 ꢁC, the reaction mixture was
allowed to come to room temperature and poured into a saturated aqueous
NH4C1 solution (300 mL). Both the layers were separated, and the aqueous layer
was extracted with Et2O (2 ꢃ 300 mL). The combined organics was dried over anhy-
drous MgSO4, and solvent was removed in vacuo. Purification of the obtained resi-
due by flash column chromatography (EtOAc–n-hexane, 1:3) afforded 2 as a pale
1
yellow liquid (63.6 g, yield 87%). IR (KBr) nmax cmꢀ1: 3285, 1463, 1061; H NMR
(300 MHz, DMSO-d6) d: 1.05 (s, 9H), 1.22 (s, 3H), 1.32 (s, 3H), 3.73 (s, 3H),
3.91–4.06 (m, 2H), 4.21 (dd, 1H), 4.30 (m, 1H), 5.24 (d, 1H, ex. D2O), 6.86 (d,
2H), 7.26 (d, 2H); 13C NMR (75 MHz, DMSO-d6) d: 25.0, 26.5, 55.1, 60.5. 65.8,
78.0, 108.8, 113.4, 129.0, 131.9, 158.3; ESI-MS: m=z (%) 221 (80), 342 (Mþ þ 1,

ASYMMETRIC SYNTHESIS OF (4S,5S)-CYTOXAZONE
2629
28
100); ½aꢄD ¼ þ 86.4 (c 1, EtOH). Elemental anal. calcd for C17H27NO4S: C, 59.80; H,
7.97; N, 4.10; S, 9.39. Found: C, 59.72; H, 7.85; N, 4.21; S, 9.09.
(2S,3S)-3-Amino-3-(4-methoxyphenyl)propane-1,2-diol
Hydrochloride (5)
A solution of MeOH-HCl (10%) (88.0 mL, 0.292 mol) was added dropwise to a
solution of protected chiral amine 2 (50.0 g, 0.146 mol) in methanol (100 ml) over a
period of 30 min. The solution was stirred for 12 h at room temperature and was then
concentrated in vacuo. The amine hydrochloride was obtained as a white solid after
precipitation from ether and was used without further purification of compound 5
(27.3 g, yield: 80%), mp 219 ꢁC (dec.); IR (KBr) nmax cmꢀ1: 3343, 3085, 3036, 1612,
1
1492, 1386, 1063, 553; H NMR (300 MHz, DMSO-d6) d: 3.22 (dd, 2H), 3.77 (s,
3H), 3.96 (m, 2H), 4.29 (d, 1H), 6.93–6.99 (d, 2H), 7.37–7.40 (d, 2H), 8.34 (s, 2H);
13C NMR (100 MHz, D2O) d: 57.0, 58.0, 63.9, 72.5, 129.5, 130.6, 131.1, 133.9;
25
ESI-MS: m=z (%) 163 (100), 198 (Mþ þ 1, 20); ½aꢄD ¼ þ3.7 ꢁ (c 1.05, MeOH).
tert-Butyl (1S,2S)-2,3-Dihydroxy-1-(4-methoxyphenyl)propyl
Carbamate (6)
TEA (27.1 g, 0.268 mol) and (Boc)2O (26.0 g, 0.128 mol) were added slowly to a
solution of b-amino alcohol 5 (25.0 g, 0.107 mol) in DCM (100.0 mL), under argon
atmosphere at 0ꢁC. After the reaction mixture was stirred at rt for 12 h, the organic
extractions were dried over MgSO4 and concentrated in vacuo to give compound 6
(28.6 g, yield: 90%) as a white solid, which was recrystallized from EtOAc–hexane;
1
mp 116–118 ꢁC; IR (KBr) nmax cmꢀ1: 3371, 1684; H NMR (300 MHz, DMSO) d:
1.35 (s, 9H), 3.22 (d, 2H), 3.60 (d, 1H), 3.72 (s, 3H), 4.44–4.66 (m, 3H), 6.84 (d,
2H), 7.17 (d, 2H); 13C NMR (DMSO, 75 MHz) d: 28.9, 55.6, 57.6, 62.4, 85.8,
25
115.0, 128.4, 133.9, 158.9; 160.6; ESI-MS: m=z 298 (Mþ þ 1, 100%); ½aꢄD ¼ þ51.0
(c 0.65, CHC13).
(4S,5S)-5-(Hydroxymethyl)-4-(4-methoxyphenyl)oxazolidin-2-one (1)
Sodium hydride (3.21 g, 1.0 mol, (60% w=w in mineral) was added to a solution
of compound 6 (25.0 g, 0.0840 mol) in anhydrous THF (100 mL) at room tempera-
ture, and the mixture was stirred under a nitrogen atmosphere for 2 h. The reaction
mixture was concentrated, CH2Cl2 was added, and the mixture was washed with
aqueous saturated NH4Cl solution and brine and dried over MgSO4. The organic
layer was concentrated by rotary evaporation, and the residue was purified by flash
column chromatography to give compound 1 (16.7 g, yield: 89%) as a white solid; mp
121–123 ꢁC; IR nmax (KBr) cmꢀ1: 3453, 2969, 1718, 1556, 1247, 1039, 861; 1H NMR
(300 MHz, DMSO-d6) d: 3.19 (m, 2H), 3.80 (s, 1H), 3.82 (s, 3H), 4.82 (d, 1H), 6.08
(d, 1H), 6.94–6.99 (d, 2H), 7.24–7.28 (d, 2H); 13C NMR (75 MHz, DMSO) d: 55.1,
56.2, 61.0, 80.0, 113.7, 128.0, 129.3, 158.7, 159.0; ESI-MS: m=z 222 (Mþ ꢀ 1, 100);
30
½aꢄD ¼ þ74.4 (c 0.86, MeOH). Elemental anal. calcd for C11H13NO4: C, 59.19; H,
5.87; N, 6.27. Found: C, 59.10; H, 5.78; N, 6.15.

2630
K. C. BABU ET AL.
ACKNOWLEDGMENT
Financial support from the Inogent Laboratories Private Limited (A GVK
BIO Company) is gratefully acknowledged.
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