A chiral pool approach for asymmetric syntheses of both antipodes of equol and sativan

Article abstract of DOI:10.1016/j.tet.2018.03.004

For the first time, both antipodes of the isoflavans, equol and sativan were synthesized in >98% ee with good overall yields starting from readily available starting materials. The chiral isoflavan, (?)-equol is produced from soy isoflavones, formonentin and daidzein by the action of intestinal bacteria in certain groups of population and other chiral isoflavans are reported from various phytochemical sources. To produce these chiral isoflavans in gram quantities, Evans’ enantioselective aldol condensation was used as a chiral-inducing step to introduce the required chirality at the C-3 position. Addition of chiral boron-enolate to substituted benzaldehyde resulted in functionalized syn-aldol products with >90% yield and excellent diastereoselectivity. Functional group transformations followed by intramolecular Mitsunobu reaction and deprotection steps resulted the target compounds, S-(?)-equol and S-(+)-sativan, with high degree of enantiopurity. By simply switching the chiral auxiliary to (S)-4-benzyloxazolidin-2-one and following the same synthetic sequence the antipodes, R-(+)-equol and R-(?)-sativan were achieved. Both enantiomers are of interest from a clinical and pharmacological perspective and are currently being developed as nutraceutical and pharmacological agents. This flexible synthetic process lends itself quite readily to the enantioselective syntheses of other biologically active C-3 chiral isoflavans.

Full text of DOI:10.1016/j.tet.2018.03.004

Accepted Manuscript
A chiral pool approach for asymmetric syntheses of both antipodes of equol and
sativan
Chinni Yalamanchili, Amar G. Chittiboyina, Sateesh Chandra Kumar Rotte, John A.
Katzenellenbogen, William G. Helferich, Ikhlas A. Khan
PII:
S0040-4020(18)30247-3
10.1016/j.tet.2018.03.004
TET 29344
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 16 November 2017
Revised Date: 28 February 2018
Accepted Date: 4 March 2018
Please cite this article as: Yalamanchili C, Chittiboyina AG, Chandra Kumar Rotte S, Katzenellenbogen
JA, Helferich WG, Khan IA, A chiral pool approach for asymmetric syntheses of both antipodes of equol
and sativan, Tetrahedron (2018), doi: 10.1016/j.tet.2018.03.004.
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A Chiral Pool Approach for Asymmetric
Syntheses of Both Antipodes of Equol and
Sativan
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Chinni Yalamanchili, Amar G. Chittiboyina*, Sateesh Chandra Kumar Rotte, John A. Katzenellenbogen,
William G. Helferich, & Ikhlas A. Khan

ACCEPTED MANUSCRIPT
A Chiral Pool Approach for Asymmetric Syntheses of Both Antipodes of
Equol and Sativan
Chinni Yalamanchili1, Amar G. Chittiboyina2*, Sateesh Chandra Kumar Rotte2, John A.
Katzenellenbogen3, William G. Helferich4, & Ikhlas A. Khan1,2
1Division of Pharmacognosy, Department of BioMolecular Science, 2National Center for Natural
Products Research; School of Pharmacy, University of Mississippi, University, Mississippi
38677, United States
3Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801,
United States
4Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL
61801, United States
amar@olemiss.edu
Abstract
For the first time, both antipodes of the isoflavans, equol and sativan were synthesized in >98 %
ee with good overall yields starting from readily available starting materials. The chiral
isoflavan, (–)-equol is produced from soy isoflavones, formonentin and daidzein by the action of
intestinal bacteria in certain groups of population and other chiral isoflavans are reported from
various phytochemical sources. To produce these chiral isoflavans in gram quantities, Evans’
enantioselective aldol condensation was used as a chiral-inducing step to introduce the required
chirality at the C-3 position. Addition of chiral boron-enolate to substituted benzaldehyde
resulted in functionalized syn-aldol products with >90% yield and excellent diastereoselectivity.
Functional group transformations followed by intramolecular Mitsunobu reaction and
deprotection steps resulted the target compounds, S-(-)-equol and S-(+)-sativan, with high degree
of enantiopurity. By simply switching the chiral auxiliary to (S)-4-benzyloxazolidin-2-one and
following the same synthetic sequence the antipodes, R-(+)-equol and R-(-)-sativan were
achieved. Both enantiomers are of interest from a clinical and pharmacological perspective and
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are currently being developed as nutraceutical and pharmacological agents. This flexible
synthetic process lends itself quite readily to the enantioselective syntheses of other biologically
active C-3 chiral isoflavans.
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Introduction
Isoflavanes are a subclass of isoflavonoids,1 characterized by a chirality at the C-3 position of the
pyran ring and are thought to be derived from the corresponding isoflavonids via reductive
processes (Figure 1). In general, isoflavans of plant origin always have an oxygen at C2' and they
almost never have oxygenation at C5.2 There are a number of isoflavans with some reported to
possess unique, promising biological activities. Examples include: sativan and vestitol isolated
from the leaves of Medicago sativa3,4 and in Lotus corniculatus;5 colutelol, isolated from the
roots of Colutea arborescens;6 lespedezol G1, isolated from the stems of Lespedeza homoloba;7
and lespecyrtin D1 isolated from the root extracts of Lespedza cyrtobotrya.8
Equol, the first isoflavan discovered, is widely considered as a dietary phytoestrogen. It was first
isolated unexpectedly from equine urine, in an attempt to isolate estrogen9,10 and later from the
urine of other animals11 and humans.12 Its absolute configuration as a S-isomer13 was assigned
after the identification of naturally occurring isoflavans S-(+)-vestitol, S-(–)-duartin, S-(–)-
mucronulatol from Dalbergia variabilis and several Macherium species.13 The S-equol is
reported to bind with several receptors14,15 including estrogen receptors (ER)16 with 13 times
16−18
more selectivity to ER subtype
β
compared to subtype
α
.
In addition to estrogenic activity,
several biological activities such as anti-fungal,19 anti-cancer,20 anti-osteoporotic, anti-
androgen,14 anti-inflammatory, anti-oxidant and anti-aging properties21 are reported and claimed
to promote brain mitochondrial function22 and to inhibit prostate growth.14
The composition of colonic microbiota have been reported to influence the metabolic fate and
biological effects of dietary intake of soy isoflavones. Indeed, the extent of at least some of the
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potential health benefits of soy intake are thought to depend on one’s capacity to convert
isoflavones to key metabolites during digestion.23,24 The gut bacteria Adlercreutzia equolifaciens
is reported produce S-equol from daidzein (2) and genistein (3).25 Studies measuring urinary
equol excretion after soy consumption indicated that equol was produced by about 25%-30% of
the adult population in Western countries compared to 50%-60% of adults living in Asian
countries and Western adult vegetarians.26,27 This high variability in equol production was
presumably attributed to inter-individual differences in the composition of the intestinal
microflora, such as A. equolifaciens.28 Moreover, it was reported that the racemic equol may not
show the same activities as that of pure enantiomers, as demonstrated in the pharmacokinetic
studies on this compound.26 Further studies of the biological and clinical properties of equol,
including our own,29,30 attest to the immense interest in this is an area of research. Given the
desirable biological properties of isoflavans, it is important to have enantiopure, gram quantities
of these isoflavans to enable further study of their biological, metabolic and pharmacokinetic
properties.
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Figure 1. Soy isoflavonoids: Isoflavones (formonentin 1, daidzein 2, genistein 3) and isoflavans
including S-(–)-equol 4.
The majority of reported syntheses were for the synthesis of a racemic form of isoflavans which
are purified by chiral separation.31-33 Examples of racemic synthesis include, catalytic
hydrogenation of isoflavans using Pd catalysts at different solvent and pH conditions.34-37
Multistep total syntheses of racemic mixtures of 5-O-methyllicoricidin,38,39 halogen-substituted
isoflavans and isoflavenes40 were also reported.41 Equol 4 was synthesized from formononetin 1
and daidzein 2 in racemic form using Pearlman’s catalyst (20% Pd(OH)2 on carbon),17 by
bacterial flora42 and from resorcinol via an isoflavene intermediate.43 Ferreira and co-workers
have demonstrated the enantioselective synthesis of the dimethoxy analogue of S-equol via α-
benzylation of N-acyl imidazolidinones.44,45 In a similar approach for introduction of the required
C–3 stereocenter, Heemstra et al. reported the enantioselective total synthesis of S-equol via
Evans’ alkylation followed by Buchwald intramolecular etherification.46 However, the key
transformations, such as Evans’ alkylation of oxazolidinone with a regiomeric mixture of
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bromobenzyl bromide and palladium-catalyzed Buchwald etherification, produced less than 50%
conversion with an overall yield <10%. S-equol 4 and other chiral isoflavans, R-sativan 5 and R-
vestitol 9, were synthesized utilizing allylic substitution47 as the chirality transfer step with the
copper reagent derived from PhMgBr and CuBrꢀMe2S. Yang et al, reported an enantioselective
iridium-catalyzed hydrogenation48 of α-arylcinnamic acids and applied the same methodology
for the synthesis of S-equol 4 with an overall yield of 48%. Recently, Jingzhao Xia et al, reported
the asymmetric hydrogenation of 2H chromenes using Ir/In-BiphPHOX catalyst to produce to
isoflavan derivatives, including S-equol in 82% yield with >95% ee.49
In continuation of our work on phytoestrogens for women’s health, several grams of
enantiomerically pure S-equol 4 and other chiral isoflavans were required. To address this need,
we report herein a scalable enantioselective synthesis of four isoflavans: equol enantiomers, (–)-
4, (+)-4, sativan isomers (+)-5 and (–)-5, using Evans’ aldol as common, chiral pool approach
(Figure 2). Unlike in Evans’ alkylation,46 Evans’ aldol addition is particularly powerful because
it establishes two contiguous stereocenters simultaneously in high yield and with a high degree
of selectivity and is reported to accommodate a wide range of substrates.
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Figure 2. Structures of the synthesized chiral isoflavans.
Results and Discussions
The retrosynthetic analysis of the chiral isoflavan scaffold is outlined in Scheme 1. The key
intermediates, syn-aldol product 8 (key intermediate to produce S-equol) or 9 (intermediate to
produce S-sativan), can be obtained via Evan’s aldol reaction between aldehydes (10 or 11) and
chiral-auxiliary substituted imides (12 or 13). Deoxygenation of the aldol product, followed by
reduction, would furnish hydroxy phenols 6 (the intermediate to produce equols) and 7 (the
intermediate to produce sativans). Cyclization under Mitsunobu conditions followed by
deprotection would produce the isoflavans, equol 4 and sativan 5.
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Scheme 1. Retrosynthesis of isoflavans, equol 4 and sativan 5 via Evans’ aldol addition to introduce chirality at C-3.
The crucial starting materials required for Evans’ aldol reaction are oxygenated benzaldehydes
(10 and 11), and benzoxazolidinone-derived imides of phenyl acetic acids [(–)-, (+)-12 and (–)-,
(+)-13]. The oxygenated aldehydes 10 and 11 were prepared from the commercially available
starting materials 17 and 18, respectively (Scheme 2). The aldehyde 10 was produced by MOM
protection of 17, whereas, the aldehyde 11 was prepared via sequential protection of 18 initially
with MOMCl at the p-hydroxy group to get 19 which was then subjected to further protection
with TBSCl. The counterpart chiral auxiliary substituted imides (–)-, (+)-12 and (–)-, (+)-13,
were synthesized according to the literature procedure in two stages.50 First, by activating the
phenyl acetic acids as acid chlorides with thionyl chloride or as mixed anhydride with pivaloyl
chloride; In the second stage, the resulting acid chloride/anhydride were then treated with the
anions of the respective 4-benzyl oxazolidinones to produce the corresponding chiral imides.
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Scheme 2. Synthesis of the starting materials for the Evans’ aldol reaction. Reagents and Conditions: a) MOMCl,
K2CO3, acetone, rt, 24 h, 94% (for 10); MOMCl, DIPEA, DCM, rt, 20 h, 75% (for 19); b) TBDMSCl,
DIPEA/DCM, 0 °C, 1h; rt, 24 h, 97%. c) For 14: SOCl2, 2h; n-BuLi, –65 to –45 °C, (+)– or (–)-16 in
º
THF, 2 h to produce (+)- or (–)-12, 73%; For 15: Pivaloyl chloride, DIPEA, THF, –78 C; n-BuLi, (+)-
or (–)-16 in THF, –78 °C, 3 h, to produce (+)- or (–)-13, 90%.
The construction of the isoflavan scaffold began with a diastereoselective Evans’ aldol
addition reaction51-53 of: benzaldehydes (10 and 11) with oxazolidinones (12 and 13,
respectively), using Bu2BOTf (Scheme 3). Typically, dialkyl boron enolates are known to
produce the (Z)-boron enolates with little sensitivity towards the base used. However, the
reactivity and stability of boron enolates resulting from 12 or 13 were found to be critical and
sensitive to temperature. No aldol addition reaction was observed at temperatures below –25 °C,
and decomposition of the aldol product was observed at reaction conditions above –10 °C.
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Scheme 3. Evans’ aldol addition to generate R-syn-aldol products (+)-8 and (+)-9. Reagents and conditions: a) add
DIPEA to (–)-12 or (–)-13 in DCM at 0 °C; cool to –25 °C, 1 M BBu2OTf in DCM (add dropwise);
warm from –25 °C to –15 °C over 30 minutes, stir for 3 h; re-cool to –25 °C, add 10 or 11 in DCM (over
30 minutes); warm from –25 °C to –15 °C (over 20 minutes), stirr for 1.5 h, 82–90%.
The reaction of enolate from (–)-12 with 4-methoxy-2-(methoxymethyl) benzaldehyde 10
furnished 2,3-syn-aldol product (+)-8 at 90% yield with >95% diastereoselectivity, evidenced by
the 1H-NMR of crude product. The superior stereochemical outcome of the aldol reaction can be
rationalized using a Zimmerman-Traxler six-membered chair-like transition state (Scheme 3). As
anticipated, the facial selectivity of the aldehyde was directed by the chiral auxiliary of the
enolate, resulting in re-face attack to produce Evans’ syn aldol product. Similarly, the reaction of
enolate from (–)-13 with benzaldehyde 11 furnished 2,3-syn-aldol product (+)-9 as a single
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diastereomer in 90% yield after purification. Deoxygenation at the benzylic hydroxyl group of
the resulting aldol product was found to be nontrivial. Several attempts to deoxygenate the aldol
products (+)-8 and (+)-9 in the presence of Pd-C/H2 in EtOAc, Pd-C/H2 in MeOH, Pd(OH)2-H2
in MeOH, HCOONH4, and Raney Ni/H2 in MeOH were unsuccessful or produced complex
mixtures with low quantities of the desired products. Conversion of the benzylic hydroxyl group
of these compounds to their corresponding tosylates was also unsuccessful. This lack of
reactivity may be due to the presence of an electron-rich aromatic system and possible chelation.
However, deoxygenation of syn-aldol product using excess of triethylsilane in the presence of
TFA, furnished the compounds in (+)-20 and (+)-22 in 81 and 75% yields, respectively. Next,
the MOM group of (+)-20 was selectively deprotected using HCl in MeOH to obtain (+)-21 in
85% yield.
The chiral auxiliary of the deoxygenated compound (+)-21 was removed by reduction
with lithium aluminum hydride, producing the diol product (+)-6 in 90% yield. Similarly, the
chiral auxiliary of the deoxygenated compound (+)-22 was reduced with LAH, and further, the
TBS group was deprotected using TBAF in THF to produce the diol (+)-7 in 89% yield. No loss
of optical purity was observed with recovered chiral auxiliaries.
The diols (+)-6 and (+)-7 were then subjected to an intramolecular Mitsunobu reaction
to produce cyclic products (–)-23 and (+)-24, respectively in 86% yield. Alternatively, refluxing
the diol with TsCl and K2CO3 in toluene also resulted the chromanes (–)-23 and (+)-24, in good
yields. The dimethoxy analogues of equol (–)-23 and MOM-protected analogues of sativan (+)-
24 were then subjected to final deprotection to yield the desired chiral products (–)-4 and (+)-5 in
>85% yields (Scheme 4).
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Scheme 4. Enantioselective synthesis of S-equol (–)-4 and S-sativan (+)-5 starting from Evans’ aldol products (+)-8
and (+)-9. Reagents and conditions: a) TFA, Et3SiH/DCM, 0 °C, 30 min (68–81%); b) 3N HCl in
MeOH/reflux, 30 min, 85%; c) for (+)-21: LiAlH4/THF, 0 °C to rt, 4 h, 90%; for (+)-22: LiAlH4/THF,0
°C to rt, overnight, TBAF/THF, 89%; d) Mitsunobu reaction: DIAD, TPP/THF, rt, 6 h, 86% or TsCl,
K2CO3, toluene, reflux, 5h, 78%; e) Deprotection: for (–)-23: Pyridinium.HCl/150 °C, overnight, 88%;
for (+)-24: 3M HCl; rt, 0.5 to 0.75 h, 86%.
By implementing the same synthetic approach (Schemes 3 and 4), the stereoselective
synthesis of the R-isomers of equol (+)-4 and sativan (–)-5 (Scheme 5) were achieved from their
respective starting materials, (+)-12 and (+)-13, via aldol intermediates (–)-8 and (–)-9, which
were subjected to the same deoxygenation, deprotection, cyclization, and deprotection steps. The
overall yield starting from their respective phenyl acetic acids and benzaldehydes were: 32% for
S-(–) and R-(+)-equol (+)-4, 28% for (+)-5 and 23% for sativan (–)-5.
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Scheme 5. Synthesis of (+)-equol 4 and (–)-sativan 5.
In conclusion, chiral isoflavans were successfully synthesized starting from phenyl acetic
acid precursors, with the aid of an Evans aldol reaction as a key transformation. The ready
availability of both antipodes of 4-benzyl-2-oxazolidinone allowed us to develop practical
synthetic sequence to access the isoflavans with high enantiopurity. Reaction of boron enolates
with oxygenated aldehydes produced in syn aldol products with excellent diastereoselectivities.
This was followed by deprotection, removal of chiral auxiliaries, cyclization and deprotection to
produce the chiral isoflavans in >30% overall yields. Furthermore, this flexible synthetic
approach allowed the synthesis of their antipodes by simply switching the chiral auxiliary. This
synthetic sequence delineates the advantage of the aldol addition reaction over the alkylation for
the efficient construction of isoflavan scaffolds with the required chirality at C3 position.
Experimental Section:
General information
All reactions were performed under an atmosphere of argon with oven-dried glassware
and standard syringe/septa techniques. All reaction mixtures were magnetically stirred with
Teflon stir bars, and temperatures were measured externally. Solvents were distilled under an
argon atmosphere prior to use. The solvents tetrahydrofuran (THF) and Et2O were distilled from
sodium benzophenone, while CH2Cl2 was dried over P2O5. Triethylamine and was distilled from
CaH2. Ethanol and methanol used were reagent-grade solvents. All reagents obtained
commercially were used without further purification. The reaction progress was monitored on
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precoated silica gel thin-layer chromatography (TLC) plates. Spots were visualized under 254
nm UV light and/or by dipping the TLC plate into a staining solution (prepared by mixing 2 mL
of anisaldehyde, 10 mL of glacial acetic acid, and 5 mL of H2SO4 in 340 mL of EtOH), followed
by heating with a heat gun. Column chromatography was performed with silica gel (230−400
mesh). All the solvents were purchased as reagent grade solvents for column chromatography.
1H and 13C NMR spectra were measured in CDCl3 or MeOH-d4 on 400 MHz (100 MHz) or 500
MHz (125 MHz) machines. Chemical shifts were reported in parts per million (ppm) downfield
from tetramethylsilane (δ) as the internal standard, and coupling constants are in hertz (Hz).
Assignment of proton resonances were confirmed by correlated spectroscopy. IR spectra were
recorded by use of a universal attenuated total reflection sampling accessory (diamond ATR) on
an Agilent Cary 630 FT-IR spectrometer. High-resolution mass spectra were recorded on an
Agilent electrospray ionization quadrupole time-of-flight (ESI-QTOF) instrument. Optical
rotations were recorded using Autopol IV (A7040-12) polarimeter.
Synthesis of the aldehydes, 10 and 11
Synthesis of the aldehyde 10
N,N-diisopropylethylamine (DIPEA) (17.0 mL, 98 mmol) was added dropwise into an ice-cold
solution of 2-hydroxy-4-methoxybenzaldehyde 17 (10g, 65.8 mmol) in dichloromethane (DCM)
(200 mL), and stirred. After 30 minutes, neat MOMCl (7.5 mL, 99 mmol) was added dropwise
and stirred further for 20 h. The reaction mixture was quenched with water (50 mL) and layers
were separated. The aqueous layer was further extracted with (2 x 50 mL) DCM and the
combined organic layers were dried over anhydrous sodium sulfate and concentrated under
vacuum to produce MOM protected aldehyde 10 (12.1 g, 61.8 mmol, 94%) as a pale yellow
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crystalline solid and used as the starting material for Evans aldol reaction without further
purification.
4-Methoxy-2-(methoxymethoxy)benzaldehyde 10:
MP: 58 °C; lit 59–60 °C;54 IR (cm—1): 2941, 2844, 1678, 1600, 1259, 1154, 1078, 987, 925 and
815; 1H NMR (400 MHz, CDCl3): δ 10.32 (s, 1H), 7.81 (d, J = 8.8 Hz, 1H), 6.70 (d, J = 2.3 Hz,
13
1H), 6.60 (dd, J = 8.8, 2.3 Hz, 1H), 5.28 (s, 2H), 3.85 (s, 3H), 3.51 (d, 3H); C NMR (100
MHz, CDCl3) δ 188.3, 166.0, 161.5, 130.3, 119.5, 107.7, 100.6, 94.7, 56.5, 55.6; ESI-HRMS:
calcd. for C10H13O4 197.0808 [M+H]+; found 197.0800.
Synthesis of the 2-((tert-Butyldimethylsilyl)oxy)-4-(methoxymethoxy)benzaldehyde 11
The aldehyde 11 was synthesized starting from 18 in two steps by following a reported
procedure.55 The first step is the synthesis of MOM protected benzaldehyde 19 and the second
step is the synthesis of 11 from 19 by TBS protection.
2-Hydroxy-4-(methoxymethoxy)benzaldehyde 19
To a suspension of dihydroxybenzaldehyde 18 (10.0g, 72.5 mmol) and anhydrous potassium
carbonate (15.0 g, 109 mmol) in acetone (150 mL) at 0 °C, MOMCl (5.5 mL, 72.4 mmol) was
added dropwise, allowed to warm to room temperature and stirred for 28 h. The reaction mixture
was filtered to remove potassium carbonate, concentrated and purified using column
chromatography to obtain MOM-protected o-hydroxy benzaldehyde 19 as brick colored crystals
(9.90 g, 54.4 mmol, 75%).
2-Hydroxy-4-(methoxymethoxy)benzaldehyde 19:
MP: 55 °C (observed); lit56 54.9 °C. IR (cm—1): 2961, 2848, 1628, 1503, 1290, 1225, 1156,
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1
1078, 992, 959 and 804; H NMR (400 MHz, CDCl3) δ 11.34 (s, 1H), 9.71 (s, 1H), 7.42 (d, J =
8.6 Hz, 1H), 6.63 (dd, J = 8.6, 2.3 Hz, 1H), 6.58 (d, J = 2.3 Hz, 1H), 5.20 (s, 2H), 3.46 (s, 3H);
ESI-HRMS: calcd. for C9H11O4 183.0652 [M+H]+; found 183.0666.
2-((tert-Butyldimethylsilyl)oxy)-4-(methoxymethoxy)benzaldehyde 11
To a solution of 2-hydroxy-4-(methoxymethoxy)benzaldehyde 19 (5.62 g, 31 mmol) and
TBDMSCl (9.31 g, 61.8 mmol) dissolved in anhydrous DCM (250 mL), DIPEA (16 mL, 92
mmol) was added and stirred at room temperature for 30 h. The reaction was then quenched with
water, extracted with DCM (2x40 mL) and the combined organic layer was dried over anhydrous
MgSO4, filtered and dried to obtain brick red colored crystals 11 (8.86 g, 30 mmol, 97%).
2-((tert-Butyldimethylsilyl)oxy)-4-(methoxymethoxy)benzaldehyde 11:
MP: 53.6 °C ; IR (cm—1): 2961, 2848, 1628, 1577, 1501, 1290, 1223, 1154, 1078, 989, and 806;
1H NMR (400 MHz, CDCl3) δ 10.29 (s, 1H), 7.75 (d, J = 8.6 Hz, 1H), 6.68 (dd, J = 8.7, 2.2 Hz,
13
1H), 6.52 (d, J = 2.2 Hz, 1H), 5.17 (s, 2H), 3.46 (s, 3H), 1.06 – 0.91 (s, 9H), 0.27 (s, 6H); C
NMR (100 MHz, CDCl3) δ 188.7, 163.4, 160.6, 129.9, 121.9, 109.8, 107.1, 94.1, 56.2, 25.7
(3C), 18.3, –4.4 (2C); ESI-HRMS: calcd. for C15H24NaO4Si 319.1342 [M+Na]+; found:
319.1289.
Synthesis of chiral imides (+)-12 and (–)-12
(+)-12 and (–)-12 were prepared from the corresponding 4-benzyloxazolidin-2-ones (+)-16 and
(–)-16 by following the reported procedure.46
(R)-4-Benzyl-3-(2-(4-methoxyphenyl)acetyl)oxazolidin-2-one (–)-12:
Yellow needles; [α]ꢁꢀꢂ = –73.3 (c = 1.20, CHCl3); MP: 88 °C; IR (cm ): 3028, 2924, 1778,
—1
1700, 1514, 1357, 1248, 1181, 1033, and 706; 1H NMR (400 MHz, CDCl3) δ 7.32–7.22 (m, 5H),
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7.17–7.09 (m, 2H), 6.92–6.85 (m, 2H), 4.72–4.61 (m, 1H), 4.33–4.11 (m, 4H), 3.80 (s, 3H), 3.26
(dd, J = 13.4, 3.3 Hz, 1H), 2.75 (dd, J = 13.4, 9.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
171.7, 159.0, 153.5, 135.3, 131.0 (2C), 129.6 (2C), 129.1 (2C), 127.5, 125.6, 114.2 (2C), 66.3,
55.5, 55.4, 40.8, 37.9; ESI-HRMS: calcd. for C19H20NO4 326.1387 [M+H]+; found: 326.1339.
(S)-4-Benzyl-3-(2-(4-methoxyphenyl)acetyl)oxazolidin-2-one (+)-12:
[α]ꢁꢀꢂ = +70.377 (c = 1.06, CHCl3); IR (cm—1): 1780, 1700, 1514, 1359, 1249, 1181, and 1033;
1H NMR (400 MHz, CDCl3) δ 7.32–7.22 (m, 5H), 7.16–7.11 (m, 2H), 6.92–6.84 (m, 2H), 4.70–
4.61 (m, 1H), 4.31–4.11 (m, 4H), 3.80 (s, 3H), 3.25 (dd, J = 13.4, 3.4 Hz, 1H), 2.75 (dd, J =
13.4, 9.4 Hz, 1H).; 13C NMR (100 MHz, CDCl3) δ 171.7, 158.9, 153.5, 135.3, 130.9 (2C), 129.5
(2C), 129.0 (2C), 127.4, 125.6, 114.2 (2C), 66.2, 55.4, 55.4, 40.8, 37.9; ESI-HRMS: calcd. for
C19H20NO4 326.1387 [M+H]+; found 326.1395.
(R)-4-Benzyl-3-(2-(2,4-dimethoxyphenyl)acetyl)oxazolidin-2-one (–)-13:
The chiral amides (–)-13 and (+)-13 were prepared by following the reported procedure by Liu
et al50 with slight modifications. For example, to a solution of 2-(2,4-dimethoxyphenyl)acetic
acid 15 (3.9 g, 20 mmol) and DIPEA (3.77 mL, 21.6 mmol) in anhydrous THF (50 mL) at –78
°C, trimethylacetyl chloride (pivaloyl chloride) (3.17 mL, 25.7 mmol) was added dropwise under
argon atmosphere. The resulting mixture was stirred for 15 min at –78 °C, 1 h at 0 °C, and then
re-cooled to –78 °C to produce mixed anhydride. Meanwhile, in a separate flask to a solution of
(R)-4-benzyl-oxazolidin-2-one [(+)16] (4.3 g, 24.3 mmol) in anhydrous THF at –78 °C under
17

ACCEPTED MANUSCRIPT
atmosphere of argon, n-BuLi (25 mmol; 10 mL of 2.5 M in hexanes) was added dropwise and
the mixture was stirred for 40 min at –78 °C. This solution was then transferred with a cannula to
the preformed mixed anhydride mixture. After stirring the reaction mixture for 15 min, it was
allowed to warm to room temperature over 2 h, then quenched with saturated aqueous NH4Cl (50
mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed
with brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel to obtain a viscous liquid 13 (6.40 g,
18 mmol, 91%).
(R)-4-Benzyl-3-(2-(2,4-dimethoxyphenyl)acetyl)oxazolidin-2-one (–)-13:
Viscous liquid [α]ꢁꢀꢂ = –76.1 (c = 1.0, CHCl3); MP: 78.9 °C; IR (cm—1): 2941, 1778, 1706,
1616, 1512, 1212, 1158 and 1037; 1H NMR (400 MHz, CDCl3) δ 7.39–7.16 (m, 5H), 7.07 (dd, J
= 7.9, 2.3 Hz, 1H), 6.54–6.42 (m, 2H), 4.68 (bt, 1H), 4.31–4.04 (m, 4H), 3.81 (s, 6H), 3.28 (dd, J
13
= 13.2, 2.5 Hz, 1H), 2.81 (dd, J = 13.2, 9.7 Hz, 1H); C NMR (100 MHz, CDCl3) δ 171.6,
160.5, 158.6, 153.8, 135.5, 131.6, 129.6 (2C), 129.0 (2C), 127.4, 115.1, 104.3, 98.8, 66.3, 55.6,
55.5 (2C), 37.9, 36.9; ESI-HRMS: calcd. for C20H22NO5 356.1492 [M+H]+; found 356.1493.
By following above procedure, the reaction between 15 and (–)-16 produced (+)-13.
(S)-4-Benzyl-3-(2-(2,4-dimethoxyphenyl)acetyl)oxazolidin-2-one (+)-13:
[α]ꢁꢀꢂ = +78.8 (c = 1.0, CHCl3), reported +113.7 (c = 1.36, CH2Cl2);57 MP: 78.9 °C ; IR (cm—1):
2939, 1178, 1708, 1616, 1592, 1512, 1393, 1367, 1212 and 1037; 1H NMR (400 MHz, CDCl3) δ
7.34–7.29 (m, 2H), 7.28–7.23 (m, 1H), 7.20 (d, J = 7.5 Hz, 2H), 7.07 (d, J = 7.9 Hz, 1H), 6.53–
18

ACCEPTED MANUSCRIPT
6.44 (m, 2H), 4.68 (ddtd, J = 9.4, 6.3, 3.2, 1.1 Hz, 1H), 4.29–4.07 (m, 4H), 3.80 (m, 6H), 3.29
13
(dd, J = 13.2, 3.2 Hz, 1H), 2.80 (dd, J = 13.2, 9.4 Hz, 1H); C NMR (100 MHz, CDCl3) δ
171.7, 160.6, 158.7, 153.8, 149.2, 135.6, 131.6, 129.6 (2C), 129.1 (2C), 127.4, 115.3, 104.5,
99.0, 66.4, 55.6, 55.5, 38.0, 36.9; ESI-HRMS: calcd. for C20H22NO 356.1492 [M+H]+; found
356.1483.
General procedure for Evans’ aldol reaction
In a 0.5 L round bottom flask, to a pre-cooled solution of chiral 4-benzyl-(acetyl)oxazolidin-2-
one (1 equiv.) in anhydrous DCM (200 mL) at 0 °C, DIPEA (1 equiv.) was added drop wise and
cooled to –25 °C. To this resulting mixture, a solution of dibutyl(((trifluoromethyl)-
sulfonyl)oxy)borane in DCM (1.0 M, 1.1 equiv.) was added drop wise to produce orange colored
solution which was warmed, over 30 min, to –15 °C and then stirred for 3h at –15 °C. The
solution was re-cooled to –25 °C and a solution of benzaldehyde (1 equiv.) in DCM (50 mL) was
added drop wise and stirred at –25 °C for 20 minutes. The temperature of the mixture was raised
to –15 °C over a period of 30 min and stirred further for additional 1 h. The mixture was
quenched with methanol (25 mL) and phosphate buffer (15 mL, pH 7.4). To this, a solution of
hydrogen peroxide (15 mL, 30%) in MeOH (35 mL) was added dropwise, warmed to room
temperature and stirred for additional 1h. The whole mixture was concentrated under reduced
pressure and the residue was diluted with water (150 mL) and extracted with diethyl ether (3 x
150 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4,
concentrated. The resulting residue was purified using column chromatography by eluting with
19

ACCEPTED MANUSCRIPT
10–25% ethyl acetate in hexanes to isolate the aldol product.
Reaction between oxazolidine-2-one (–)-12 and aldehyde 10 produced (+)-8 as a viscous liquid
in 90% yield.
(R)-4-Benzyl-3-((2R,3R)-3-hydroxy-3-(4-methoxy-2-(methoxymethoxy)phenyl)-2-(4-
methoxyphenyl)propanoyl)oxazolidin-2-one (+)-8:
[α]ꢁꢀꢂ = +97 (c = 0.12, CHCl3); IR (cm—1): 3529, 2956, 2935, 1777, 1611, 1510, 1156, 1000,
1
998, 732 and 704; H NMR (500 MHz, CDCl3) δ 7.29 (d, J = 8.7 Hz, 2H), 7.22–7.18 (m, 3H),
7.02 (d, J = 8.5 Hz, 1H), 6.99–6.95 (m, 2H), 6.88–6.84 (m, 2H), 6.72 (d, J = 2.4 Hz, 1H), 6.42
(dd, J = 8.5, 2.4 Hz, 1H), 5.54 (s, 2H), 5.25–5.19 (dd, J = 16.0Hz, 2H), 4.60 (ddt, J = 9.1, 7.1,
3.5 Hz, 1H), 4.06–3.97 (m, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 3.54 (s, 3H), 3.09 (dd, J = 13.5, 3.4
Hz, 1H), 2.55 (dd, J = 13.5, 9.1 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 173.7, 160.1, 159.1,
155.2, 152.5, 134.8, 131.1 (2C), 129.4 (2C), 129.1, 128.8 (2C), 127.2, 126.3, 121.8, 113.7 (2C),
106.0, 101.1, 94.7, 70.8, 65.7, 56.3, 55.3, 55.2, 54.7, 53.1, 37.2; ESI-HRMS: calcd. for
C29H30NO7 [M+H-H20]+ 504.2017; found 504.2030.
Reaction between oxazolidine-2-one (+)-12 and aldehyde 10 produced (–)-8.
(S)-4-Benzyl-3-((2S,3S)-3-hydroxy-3-(4-methoxy-2-(methoxymethoxy)phenyl)-2-(4-
methoxyphenyl)propanoyl)oxazolidin-2-one (–)-8:
Yield 89%; [α]ꢁꢀꢂ = –111.3 (c = 0.39, CHCl3); IR (cm—1): 3528, 2957, 2838, 1777, 1611, 1510,
1
1156, and 1000; H NMR (500 MHz, CDCl3) δ 7.30 (d, J = 8.7 Hz, 2H), 7.23–7.17 (m, 3H),
7.03 (d, J = 8.5 Hz, 1H), 7.00–6.94 (m, 2H), 6.86 (d, J = 8.7 Hz, 2H), 6.73 (d, J = 2.4 Hz, 1H),
6.42 (dd, J = 8.5, 2.4 Hz, 1H), 5.54 (s, 2H), 5.30–5.21 (m, 2H), 4.60 (ddt, J = 8.9, 7.2, 3.6 Hz,
20

ACCEPTED MANUSCRIPT
1H), 4.06–3.97 (m, 2H), 3.79 (s, 3H), 3.76 (s, 3H), 3.54 (s, 3H), 3.08 (dd, J = 13.5, 3.4 Hz, 1H),
2.56 (dd, J = 13.5, 9.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 173.7, 160.1, 159.1, 155.2,
152.5, 134.8, 131.1 (2C), 129.4 (2C), 129.1, 128.8 (2C), 127.2, 126.3, 121.9, 113.7 (2C), 106.0,
101.1, 94.7, 70.8, 65.7, 56.3, 55.3, 55.2, 54.7, 53.1, 37.2; ESI-HRMS: calcd. for C29H30NO7
504.2017 [M+H-H20]+; found 504.1997.
Similarly, the reaction between oxazolidine-2-one (–)-13 and aldehyde 11 produced (+)-9 as
amorphous solid in 82% yield.
(R)-4-Benzyl-3-((2R,3R)-3-(2-((tert-butyldimethylsilyl)oxy)-4-(methoxymethoxy)phenyl)-2-
(2,4-dimethoxyphenyl)-3-hydroxypropanoyl)oxazolidin-2-one (+)-9:
MP: 72.9 °C; [α]ꢁꢀꢂ = +203.5 (c = 1.0, CHCl3); IR (cm—1): 3542, 2931, 2857, 1791, 1674, 1613,
1588, 1508, 1389, 1212, and 1160; 1H NMR (400 MHz, CDCl3) δ 7.38–7.21 (m, 3H), 7.20–7.10
(m, 2H), 7.06 (d, J = 8.3 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.56–6.51 (m, 1H), 6.48–6.41 (m,
2H), 6.35–6.30 (m, 1H), 5.63 (d, J = 3.6 Hz, 1H), 5.47 (d, J = 4.1 Hz, 1H), 5.09 (s, 2H), 4.72–
4.62 (m, 1H), 4.01 (d, J = 5.5 Hz, 2H), 3.79 (s, 3H), 3.71 (s, 1H), 3.44 (s, 3H), 3.42 (s, 3H), 3.35
(dd, J = 13.3, 3.5 Hz, 1H), 2.53 (dd, J = 13.3, 10.0 Hz, 1H), 1.00 (s, 9H), 0.34 (s, 3H), 0.32 (s,
13
3H); C NMR (100 MHz, CDCl3) δ 175.1, 160.3, 159.3, 157.1, 153.2, 152.0, 135.5, 131.1,
129.5 (2C), 129.1 (2C), 128.4, 127.4, 125.4, 114.5, 108.1, 106.2, 103.8, 98.6, 94.7, 69.0, 66.0,
55.9, 55.4, 55.2 (2C), 48.2, 37.8, 25.9 (3C), 18.4, –3.9, –4.1; ESI-HRMS: calcd. for
C35H44NO8Si 634.2831[M+H-H2O]+; found 634.2827.
The reaction between oxazolidine-2-one (+)-13 and aldehyde 11 produced (–)-9 in 85% yield.
21

ACCEPTED MANUSCRIPT
(S)-4-Benzyl-3-((2S,3S)-3-(2-((tert-butyldimethylsilyl)oxy)-4-(methoxymethoxy)phenyl)-2-(2,4-
dimethoxyphenyl)-3-hydroxypropanoyl)oxazolidin-2-one (–)-9:
Colorless amorphous solid; [α]ꢁꢀꢂ = –201.4 (c = 1.0, CHCl3); MP:74.6 °C; IR (cm—1): 3540,
2931, 1790, 1672, 1611, 1508, 1366, 1292, 1212 and 1158; 1H NMR (400 MHz, CDCl3) δ 7.36–
7.19 (m, 3H), 7.20–7.11 (m, 2H), 7.06 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 8.5 Hz, 1H), 6.53 (d, J =
2.2 Hz, 1H), 6.48–6.39 (m, 2H), 6.32 (d, J = 2.2 Hz, 1H), 5.63 (bt, 1H), 5.47 (d, J = 3.6 Hz, 1H),
5.09 (s, 2H), 4.72–4.61 (m, 1H), 4.01 (d, J = 5.4 Hz, 2H), 3.78 (s, 3H), 3.71 (d, J = 3.0 Hz, 1H),
3.44 (s, 3H), 3.42 (s, 3H), 3.34 (dd, J = 13.2, 2.8 Hz, 1H), 2.53 (dd, J = 13.2, 10.2 Hz, 1H), 1.00
13
(s, 9H), 0.34 (s, 3H), 0.32 (s, 3H); C NMR (100 MHz, CDCl3) δ 175.1, 160.3, 159.3, 157.1,
153.2, 152.0, 135.5, 131.1, 129.5 (2C), 129.0 (2C), 128.3, 127.4, 125.4, 114.5, 108.1, 106.2,
103.8, 98.6, 94.7, 69.0, 66.0, 55.9, 55.4, 55.2 (2C), 48.2, 37.8, 25.9 (3C), 18.4, –3.9, –4.1; ESI-
HRMS: calcd. for C35H44NO8Si 634.2831 [M+H-H20]+; found 634.2817.
Deoxygenation of the aldol products
To a solution of the aldol adduct (R)-4-benzyl-3-((2R,3R)-3-hydroxy-3-(4-methoxy-2-
(methoxymethoxy)phenyl)-2-(4-methoxyphenyl)propanoyl)oxazolidin-2-one (+)-8 (1.04 g, 2
mmol) in dichloromethane (10 mL) cooled at 0 °C, triethyl silane (10 mL, 62.6 mmol) was added
dropwise and stirred for 10 min. To this mixture, trifluoroacetic acid (1 mL, 13 mmol) was added
drop-wise in two installments, allowed to warm to room temperature, and the reaction was
monitored using TLC. After 30 min, the reaction was cooled to 0 °C and quenched using
NaHCO3 (10 mL) and extracted with dichloromethane (2 x 15mL). The combined organic layers
were dried over anhydrous MgSO4, concentrated and purified using column chromatography to
22

ACCEPTED MANUSCRIPT
obtain a colorless viscous liquid (+)-20 (0.81 g, 1.60 mmol, 81%).
(R)-4-Benzyl-3-((S)-3-(4-methoxy-2-(methoxymethoxy)phenyl)-2-(4-
methoxyphenyl)propanoyl)oxazolidin-2-one (+)-20:
[α]ꢁꢀꢂ = +24.0 (c = 0.15, CHCl3); IR (cm—1): 2933, 2836, 1778, 1695, 1613, 1510, 1218, 1156,
and 1007; 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.4 Hz, 2H), 7.22–7.15 (m, 3H), 7.02–6.92
(m, 3H), 6.87 (d, J = 8.4 Hz, 2H), 6.68 (d, J = 2.5 Hz, 1H), 6.39 (dd, J = 8.3, 2.5 Hz, 1H), 5.41
(dd, J = 8.8, 6.2 Hz, 1H), 5.18 (s, 2H), 4.63 (tt, J = 7.6, 3.5 Hz, 1H), 4.07–3.95 (m, 2H), 3.80 (s,
3H), 3.75 (s, 3H), 3.52 (s, 3H), 3.35 (dd, J = 13.6, 8.8 Hz, 1H), 3.13–2.98 (m, 2H), 2.56 (dd, J =
13.6, 8.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 173.9, 159.4, 158.8, 156.4, 152.7, 135.1,
131.3 , 130.8, 129.8 (2C), 129.4 (2C), 128.8(2C), 127.1, 120.2, 113.9 (2C), 105.8, 101.0, 94.6,
65.6, 56.1, 55.3, 55.2, 54.9, 47.9, 37.4, 34.4; ESI-HRMS: calcd. for C29H32NO7 506.2173
[M+H]+; found 506.2176.
The deoxygenation of (–)-8 produced (–)-20 as a viscous liquid in 75% yield.
(S)-4-Benzyl-3-((R)-3-(4-methoxy-2-(methoxymethoxy)phenyl)-2-(4-
methoxyphenyl)propanoyl)oxazolidin-2-one (–)-20:
1
1
[α]ꢁꢀꢂ = -26.4 (c = 0.33, CHCl3); IR (cm ): 2933, 1178, 1695, 1510, 1218, 1156 and 1007; H
NMR (500 MHz, CDCl3) δ 7.36 (d, J = 8.7 Hz, 2H), 7.24–7.16 (m, 3H), 7.00–6.93 (m, 3H), 6.87
(d, J = 8.7 Hz, 2H), 6.68 (d, J = 2.4 Hz, 1H), 6.39 (dd, J = 8.3, 2.5 Hz, 1H), 5.41 (dd, J = 8.8, 6.2
Hz, 1H), 5.19 (s, 2H), 4.63 (ddt, J = 8.9, 7.7, 3.3 Hz, 1H), 4.06–3.98 (m, 2H), 3.80 (s, 3H), 3.75
(s, 3H), 3.51 (s, 3H), 3.34 (dd, J = 13.4, 8.9 Hz, 1H), 3.09–3.01 (m, 2H), 2.56 (dd, J = 13.5, 9.0
—
13
Hz, 1H). C NMR (125 MHz, CDCl3) δ 174.0, 159.6, 158.9, 156.5, 152.9, 135.2, 131.5, 130.9,
23

ACCEPTED MANUSCRIPT
129.9 (2C), 129.6 (2C), 128.9 (2C), 127.3, 120.3, 114.1 (2C), 105.9, 101.1, 94.6, 65.7, 56.3,
55.4, 55.4, 55.0, 48.1, 37.5, 34.6; ESI-HRMS: calcd. for C29H32NO7 506.2173 [M+H]+; found
506.2151.
Deoxygenation of (+)-9 produced (+)-22 as a crystalline solid in 73% yield.
(R)-4-Benzyl-3-((S)-3-(2-((tert-butyldimethylsilyl)oxy-4-(methoxymethoxy)phenyl)-2-(2,4-
dimethoxyphenyl)propanoyl)oxazolidin-2-one (+)-22:
MP: 107.5 °C; [α]ꢁꢀꢂ = +11.6 (c = 1.0, CHCl3); IR (cm—1): 2931, 1784, 1696, 1611, 1506, 1292,
1210 and 1156; 1H NMR (400 MHz, CDCl3) δ 7.36–7.21 (m, 4H), 7.19–7.11 (m, 2H), 6.89 (d, J
= 8.2 Hz, 1H), 6.54 (d, J = 2.4 Hz, 1H), 6.50–6.46 (m, 2H), 6.42 (d, J = 2.4 Hz, 1H), 5.54 (t, J =
7.6 Hz, 1H), 5.15–5.01 (m, 2H), 4.60 (ddt, J = 10.7, 7.4, 3.2 Hz, 1H), 3.98–3.90 (m, 2H), 3.80 (s,
3H), 3.68 (s, 3H), 3.44 (s, 3H), 3.34–3.24 (m, 2H), 3.03 (dd, J = 13.3, 7.3 Hz, 1H), 2.55 (dd, J =
13
13.2, 10.0 Hz, 1H), 1.01 (s, 9H), 0.30 (s, 3H), 0.29 (s, 3H); C NMR (100 MHz, CDCl3) δ
174.9, 159.9, 158.3, 156.5, 154.7, 152.4, 135.7, 131.0, 129.5, 129.3 (2C), 128.9 (2C), 127.2,
123.1, 120.1, 108.1, 107.1, 104.1, 98.6, 94.6, 65.7, 55.8, 55.6, 55.4, 55.3, 42.7, 37.7, 32.5, 25.9
(3C), 18.3, –4.1, –4.2; ESI-HRMS: calcd. for C35H46NO8Si 636.2987 [M+H]+; found 636.2995.
Deoxygenation of (–)-9 produced (–)-22 as a crystalline solid in 68% yield.
(S)-4-Benzyl-3-((R)-3-(2-((tert-butyldimethylsilyl)oxy)-4-(methoxymethoxy)phenyl)-2-(2,4-
dimethoxyphenyl)propanoyl)oxazolidin-2-one (–)-22:
1
MP: 106.9 °C; [α]ꢁꢀꢂ = –10.7 (c = 1.0, CHCl3); IR (cm ): 2957, 2935, 1788, 1698, 1613, 1508,
—
1
1292, 1212, 1158 and 1018; H NMR (400 MHz, CDCl3) δ 7.32–7.23 (m, 4H), 7.21–7.13 (m,
24

ACCEPTED MANUSCRIPT
2H), 6.88 (d, J = 8.3 Hz, 1H), 6.53 (d, J = 2.4 Hz, 1H), 6.48 (dd, J = 8.4, 2.4 Hz, 2H), 6.42 (d, J
= 2.4 Hz, 1H), 5.53 (t, J = 7.7 Hz, 1H), 5.17–5.01 (m, 2H), 4.60 (ddt, J = 10.6, 6.7, 3.1 Hz, 1H),
3.98-3.90 (m, 2H), 3.81 (s, 3H), 3.68 (s, 3H), 3.45 (s, 3H), 3.34–3.23 (m, 2H), 3.02 (dd, J = 13.3,
7.3 Hz, 1H), 2.55 (dd, J = 13.3, 10.0 Hz, 1H), 1.01 (s, 9H), 0.29 (s, 3H), 0.28 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 174.9, 159.9, 158.3, 156.5, 154.8, 152.4, 135.8, 131.0, 129.5, 129.3 (2C),
128.9 (2C), 127.2, 123.2, 120.1, 108.1, 107.1, 104.1, 98.6, 94.6, 65.7, 55.8, 55.6, 55.4, 55.3,
42.7, 37.7, 32.5, 25.9 (3C), 18.3, –4.1, –4.2; ESI-HRMS: calcd. for C35H46NO8Si 636.2987
[M+H]+; found 636.2979.
Deprotection of MOM group
A solution of deoxygenated aldol product (+)-20 (1 g, 1.98 mmol) dissolved in 3 M HCl in
methanol (10 mL) was refluxed and the reaction was monitored by TLC. After 30 min, the
reaction was cooled to 0 °C, quenched with saturated NaHCO3 (10 mL), methanol and was
evaporated. The reaction mixture was extracted using ethyl acetate (2 x 20 mL) and the
combined organic layer was dried over anhydrous MgSO4, concentrated and purified using
column chromatography to obtain phenol (+)-21 as a colorless viscous (0.78 g, 1.7 mmol, 85%).
(R)-4-Benzyl-3-((S)-3-(2-hydroxy-4-methoxyphenyl)-2-(4-ethoxyphenyl)propanoyl)oxazolidin-
2-one (+)-21:
[α]ꢁꢀꢂ = +37.1 (c = 0.21, CHCl3); IR (cm—1): 3388, 2928, 1777, 1695, 1620, 1510, 1164, 1181,
and 1033; 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 8.7 Hz, 2H), 7.25–7.15 (m, 4H), 7.03 (d, J
= 8.3 Hz, 1H), 6.99–6.88 (m, 4H), 6.48 (d, J = 2.5 Hz, 1H), 6.45 (dd, J = 8.3, 2.6 Hz, 1H), 5.21
(dd, J = 11.0, 4.3 Hz, 1H), 4.68 (tt, J = 8.5, 3.3 Hz, 1H), 4.09 (t, J = 8.5 Hz, 1H), 4.02 (dd, J =
25

ACCEPTED MANUSCRIPT
9.1, 3.1 Hz, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 3.45 (dd, J = 14.3, 11.1 Hz, 1H), 3.07 (dd, J = 13.5,
13
3.5 Hz, 1H), 2.76 (dd, J = 14.4, 4.3 Hz, 1H), 2.56 (dd, J = 13.5, 8.9 Hz, 1H); C NMR (100
MHz, CDCl3) δ 175.8, 159.7, 159.1, 155.1, 152.3, 134.6, 131.9, 130.2, 129.6 (2C), 129.4 (2C),
128.9 (2C), 127.3, 117.8, 114.3 (2C), 107.0, 102.8, 65.7, 55.3, 55.2, 54.8, 50.8, 37.1, 33.9; ESI-
HRMS: calcd. for C27H28NO6 462.1911 [M+H]+; found 462.1917.
MOM group deprotection of (–)-20 produced (–)-21 as viscous liquid in 87% yield.
(S)-4-benzyl-3-((R)-3-(2-hydroxy-4-methoxyphenyl)-2-(4-methoxyphenyl)propanoyl)oxazolidin-
2-one (–)-21:
1
[α]ꢁꢀꢂ = –34.7 (c = 0.15, CHCl3); IR (cm ): 3388, 2928, 1777, 1695, 1620, 1510, 1181 and
—
1
1033; H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 8.6 Hz, 2H), 7.26–7.13 (m, 4H), 7.03 (d, J =
8.3 Hz, 1H), 6.97–6.93 (m, 2H), 6.92 (d, J = 8.6 Hz, 2H), 6.48 (d, J = 2.5 Hz, 1H), 6.45 (dd, J =
8.3, 2.6 Hz, 1H), 5.21 (dd, J = 11.0, 4.3 Hz, 1H), 4.68 (tt, J = 8.5, 3.3 Hz, 1H), 4.09 (t, J = 8.5
Hz, 1H), 4.02 (dd, J = 9.1, 3.1 Hz, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 3.45 (dd, J = 14.3, 11.0 Hz,
1H), 3.07 (dd, J = 13.5, 3.5 Hz, 1H), 2.77 (dd, J = 14.4, 4.3 Hz, 1H), 2.56 (dd, J = 13.5, 8.9 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 175.9, 159.9, 159.2, 155.3, 152.5, 134.8, 132.0, 130.3 (2C),
129.8 (2C), 129.5 (2C), 129.0 (2C), 127.4, 118.0, 114.4 (2C), 107.1, 102.9, 65.9, 55.4, 55.4,
55.0, 50.9, 37.3, 34.1. ESI-HRMS: calcd. for C27H28NO6 462.1911 [M+H]+; found 462.1891.
Reduction
(S)-2-(3-Hydroxy-2-(4-methoxyphenyl)propyl)-5-methoxyphenol (+)-6
To a suspension of LiAlH4 (4 g, 105 mmol) in THF (25 mL) at 0 °C, solution of the compound
26

ACCEPTED MANUSCRIPT
(+)-21 (24 g, 52 mmol) in THF (150 mL) was added dropwise and stirred for 4 hours at room
temperature. Then the reaction was cooled to 0 °C and carefully quenched with a dropwise
addition of saturated NaOH (50 mL). THF was evaporated and the resulting solution was
extracted with ethyl acetate (3 x 50 mL) and separated, dried over anhydrous MgSO4 and
isolated using flash chromatography to produce colorless liquid (+)-6 (13.5 g, 47 mmol, 90%),
which was solidified on standing.
(S)-2-(3-Hydroxy-2-(4-methoxyphenyl)propyl)-5-methoxyphenol (+)-6:
1
ꢁꢂ
—
[α]ꢀ = +31.6 (c = 0.185, CHCl3); IR (cm ): 3342, 2930, 2836, 1614, 1510, 1441, 1285, 1242,
1
1178, 1031, 958, and 828; H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 8.8 Hz, 2H), 6.86 (d, J =
8.8 Hz, 2H), 6.81 (d, J = 8.5 Hz, 1H), 6.44 (d, J = 2.5 Hz, 1H), 6.39 (dd, J = 8.3, 2.5 Hz, 1H),
3.80 (s, 3H), 3.74 (bs, 5H), 3.08 (dd, J = 13.5, 8.4 Hz, 1H), 2.98 (dq, J = 9.9, 4.8 Hz, 1H), 2.82
13
(dd, J = 13.5, 5.0 Hz, 1H); C NMR (100 MHz, CDCl3) δ 159.4, 158.4, 155.5, 134.6, 131.9,
128.8 (2C), 118.0, 114.0 (2C), 106.3, 102.1, 65.1, 55.3, 55.3, 47.5, 31.5; ESI-HRMS: calcd. for
C17H21O4 289.1434 [M+H]+; found 289.1433.
Reduction of (–)-21 with LAH produced (–)-6 as a viscous liquid and solidified on standing.
(R)-2-(3-Hydroxy-2-(4-methoxyphenyl) propyl)-5-methoxyphenol (–)-6:
1
[α]ꢁꢀꢂ = –33.3 (c = 0.19, CHCl3); IR (cm ): 3351, 2931, 2836, 1737, 1615, 1511, 1441, 1285,
—
1243, 1159, 1108, 1032, 958, and 829; 1H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 8.6 Hz, 2H),
6.86 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 8.3 Hz, 1H), 6.44 (d, J = 2.5 Hz, 1H), 6.39 (dd, J = 8.3, 2.6
Hz, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 3.74 (t, 2H), 3.08 (dd, J = 13.6, 8.5 Hz, 1H), 2.98 (dq, J =
13
9.9, 5.0 Hz, 1H), 2.82 (dd, J = 13.6, 5.0 Hz, 1H); C NMR (100 MHz, CDCl3) δ 159.4, 158.4,
155.6, 134.6, 131.9, 128.8 (2C), 117.9, 114.0 (2C), 106.3, 102.1, 65.1, 55.3, 55.2, 47.4, 31.4;
27

ACCEPTED MANUSCRIPT
ESI-HRMS: calcd. for C17H21O4 289.1434 [M+H]+; found 289.1441.
(S)-2-(2-(2,4-Dimethoxyphenyl)-3-hydroxypropyl)-5-(methoxymethoxy)phenol (+)-7
To a suspension of LiAlH4 (0.2 g, 5.13 mmol) in 15 mL THF (15 mL) at 0 °C, solution of (R)-4-
benzyl-3-((S)-3-(2-((tert-butyldimethylsilyl)oxy-4-(methoxy-methoxy)phenyl)-2-(2,4-
dimethoxyphenyl)propanoyl)oxazolidin-2-one (+)-22 (1.18 g, 1.86 mmol) in THF (50 mL) was
added dropwise and stirred overnight at room temperature. Then the reaction was cooled to 0 °C,
and quenched with the careful addition of saturated NaOH (10 mL) and extracted with ethyl
acetate (3 x 20 mL). The combined organic layers were dried over anhydrous MgSO4. TLC
indicated a mixture of the expected alcohol along with monosilylated alcohol as the major
product. Without further purification, the mixture was subjected to desilylation using TBAF in
THF. After workup, the crude mixture was purified using flash chromatography to produce diol
(+)-7 (0.58 g, 1.65 mmol, 89%) as a colorless, viscous liquid.
(S)-2-(2-(2,4-Dimethoxyphenyl)-3-hydroxypropyl)-5-(methoxymethoxy)phenol (+)-7:
Yield 89%; Colorless viscous liquid, [α]ꢁꢀꢂ = +26.9 (c = 1.0, CHCl3); IR (cm-1): 3362, 2954,
1615, 1588, 1508, 1467, 1292, 1210 and 1156; 1H NMR (400 MHz, CDCl3) δ 7.14 (d, J = 8.3
Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 6.60 (d, J = 2.4 Hz, 1H), 6.55–6.41 (m, 3H), 5.12 (s, 2H), 3.82
(s, 3H), 3.80 (s, 3H), 3.80–3.66 (m, 3H), 3.47 (s, 3H), 3.32 (dt, J = 9.6, 4.6 Hz, 1H), 3.04 (dd, J =
14.0, 9.6 Hz, 1H), 2.74 (dd, J = 14.0, 4.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 159.5, 157.7,
156.9, 155.8, 131.7, 128.5, 123.4, 119.8, 108.3, 104.5, 104.2, 98.9, 94.4, 63.5, 55.9, 55.5, 55.4,
41.3, 30.5; ESI-HRMS: calcd. for C19H25O6 349.1646 [M+H]+; found 349.1655.
28