Total syntheses of racemic and natural glycinol

Article abstract of DOI:10.1021/np900509f

Total syntheses of racemic and (-)-glycinol (1) are described. A Wittig reaction produced the isoflav-3-ene from which a Sharpless dihydroxylation introduced either the racemic or enantiomeric 6a-hydroxy group. A 5.5% overall yield of racemic material was obtained after 12 steps. A method was devised for a one-pot switch of protecting groups masking a sensitive resorcinolic para-functionality, and conditions were optimized to prompt spontaneous closure of the pterocarpanolic dihydrofuran upon subsequent exposure of its ortho-functionality. These improvements eliminated two steps and increased the overall yield to 9.8% during production of the natural enantiomer.

Full text of DOI:10.1021/np900509f

2072
J. Nat. Prod. 2009, 72, 2072–2075
Total Syntheses of Racemic and Natural Glycinol
Amarjit Luniwal, Rahul S. Khupse, Michael Reese, Lei Fang, and Paul W. Erhardt*
Center for Drug Design and DeVelopment, Department of Medicinal and Biological Chemistry, The UniVersity of Toledo College of Pharmacy,
Toledo, Ohio 43606-3390
ReceiVed August 17, 2009
Total syntheses of racemic and (-)-glycinol (1) are described. A Wittig reaction produced the isoflav-3-ene from which
a Sharpless dihydroxylation introduced either the racemic or enantiomeric 6a-hydroxy group. A 5.5% overall yield of
racemic material was obtained after 12 steps. A method was devised for a one-pot switch of protecting groups masking
a sensitive resorcinolic para-functionality, and conditions were optimized to prompt spontaneous closure of the
pterocarpanolic dihydrofuran upon subsequent exposure of its ortho-functionality. These improvements eliminated two
steps and increased the overall yield to 9.8% during production of the natural enantiomer.
Glycinol (1) is a key intermediate in the biosynthetic pathway
leading to the glyceollin family of natural products.1 These 6a-
hydroxypterocarpans are phytoalexins2 that become elicited in low
amounts when soybeans are subjected to specific types of stress.3
Our collaborators have shown that the most prevalent member of
this family, glyceollin I (2), is also the most prominent in exhibiting
antiestrogenic (antagonist) properties that may be useful to prevent
or treat breast cancer.4 Alternatively, in recent studies they have
demonstrated that 1 exhibits potent estrogenic (agonist) activity,5
thus confirming an earlier hypothesis6 and, in turn, suggesting that
this particular member may instead be useful as a selective estrogen
receptor modulating agent, or SERM, during hormone replacement
therapy.5,7 Corresponding efforts in our laboratory have been
directed toward synthesizing the various glyceollin family members
and their analogues in quantities conducive to further structure-
activity relationship studies.8
(Ph3P·HBr) in five, 0.2 molar equiv portions so as to better preserve
the MOM protecting group during the course of the internal Wittig
reaction (step d). In the next two steps (e and f) leading to 10, we
were able to devise a one-pot procedure for the exchange of MOM
with TBDMS as opposed to our previous purification of intermedi-
ate 9, which is susceptible to spontaneous decomposition during
workup. Thus, after taking advantage of our novel deprotection
method that utilizes Ph3P·HBr in dichloromethane to gently remove
MOM within the course of a few hours (TLC showing disappear-
ance of 8),8g Et3N followed by TBDMSCl was added to the same
reaction flask, which was then allowed to stir overnight. In addition
to providing for a more facile process, the yield from 8 to 10 was
increased by nearly 15%.
While the non-asymmetric conversion of 10 to 11 can be
accomplished by deploying only catalytic amounts of osmium
tetroxide (OsO4) without chiral catalyst, a nearly equal stoichiometry
of OsO4, substrate, and (DHQD)2PHAL is required in order to
thoroughly establish the (6aS, 11aS) stereochemistry present in this
family’s natural enantiomers.8g,11,12 During our asymmetric syn-
thesis we found that commercial supplies of this chiral catalyst had
become limited. This prompted us to prepare our own catalyst. The
latter followed literature procedures,13 which proceeded unevent-
fully in high yield from readily available starting materials and,
ultimately, resulted in a fortuitous reduction in overall cost.
Intermediate 11 exhibited greater than 98% enantiomeric excess
(ee) when determined by chiral HPLC.14 The excellent separation
of these enantiomers, as well as those for 1, and the distinctly
diagnostic peaks obtained from the latter’s forced decomposition
are noteworthy. These methods can serve as useful analytical tools
during future syntheses in this arena (specific results and analytical
details are provided in the Supporting Information).
Although we previously found it more convenient to isolate 12
while on route to 13 from 11,8g we further investigated the
possibility of allowing the ring closure to occur spontaneously upon
debenzylation of the resorcinolic ortho-hydroxy group. This
maneuver has been successful in the hands of others when preparing
different pterocarpanoid natural products,12d,15 and we were able
to establish conditions that optimized this one-pot transformation
relative to 13. Thus, by changing the reaction solvent during
hydrogenolysis from acetone to anhydrous EtOH and by increasing
the hydrogen pressure from 15 to 35 psi so as to allow equivalent
reaction times, at least 85% yields of cyclized material 13 can be
obtained rather than high yields of 12. This remarkable solvent
effect may be due to enhanced solvation of the polar transition state
during nucleophilic attack by the resorcinolic ortho-hydroxy-oxygen
atom on the proposed quinone-methide formed as a transient species
prior to cyclization.8g Alternatively, anhydrous ethanol may better
sequester the water byproduct and thus serve to drive the cyclization
First identified by Lyne and Mulheirn in 1978 as a minor
constituent in CuCl2-treated soybean cotyledons,9 1 was given its
trivial name in 1984 by Weinstein et al., who used bacteria and
ultraviolet light to elicit the compound and then studied its activity
against a variety of microorganisms.10 Owing in part to the low
amounts of material, further characterization of 1’s biological
properties has lagged. This situation, coupled with the recent
demonstration of its interesting SERM activity,5 prompted our
production of 1 by total synthesis from commercially available
materials. Our route is shown in Scheme 1, where the longer path
that includes all steps is analogous to the synthesis of glyceollin I,
which we previously elaborated from 13 in two steps (dotted
lines).8g This path was followed to prepare racemic materials for
use as chiral chromatography standards while also conducting
process chemistry enhancements. The latter resulted in the shorter
route depicted in Scheme 1, which deploys two one-pot reactions
(steps g and k). With these two modifications and other process
improvements, the shorter route nearly doubled the overall yield
when it was applied toward preparing (-)-1.
The steps leading to 8 were conducted as before except that we
found it beneficial to add triphenylphosphine hydrobromide
* Corresponding author. Tel: (419) 530-2167. Fax: (419) 530-7946.
E-mail: paul.erhardt@utoledo.edu.
10.1021/np900509f CCC: $40.75  2009 American Chemical Society and American Society of Pharmacognosy
Published on Web 11/04/2009

Notes
Journal of Natural Products, 2009, Vol. 72, No. 11 2073
Scheme 1. Synthetic Routes Used to Prepare Racemic and Natural 1a
a (a) (i) MOMCl, K2CO3, Me2CO, rt, (ii) BnBr, K2CO3, Me2CO, reflux, (iii) I2, Selectfluor, MeOH, rt, 50% over three steps; (b) (i) BnBr, NaHCO3, CH3CN, 60 °C,
(ii) NaBH4, MeOH, rt, 61% over two steps; (c) K2CO3, Me2CO, reflux, 72%; (d) (i) PPh3 · HBr (added in portions), CH3CN, rt, (ii) t-BuONa, MeOH, reflux, 70% over
two steps; (e) PPh3 · HBr, CH3CN, water, reflux, 78%; (f) TBDMSCl, Et3N, CH2Cl2, rt, 69%; (g) PPh3 · HBr, CH2Cl2, rt, then Et3N, TBDMSCl, rt, 70%; (h) OsO4,
(DHQD)2PHAL, CH2Cl2, -20 °C, 86%; (i) 10% Pd-C, H2, Me2CO, 15 psi, rt, 89%; (j) polymeric base, 4 Å MS, EtOH, 80 °C, 60%; (k) 10% Pd-C, H2, EtOH, 35
psi, rt, 85%; (l) Et3N · 3HF, pyridine, pH 5-6, CH2Cl2/MeOH (5:1), rt, 78%.
purification. Acetone was dried over 4 Å molecular sieves. Tetrahy-
drofuran (THF) was distilled under nitrogen over sodium-benzophenone.
Thin-layer chromatography (TLC) was done on 250 µm fluorescent
SiO2 TLC plates and visualized by using UV light or iodine vapor.
Normal-phase flash CC was performed using silica gel (200-425 mesh
60 Å pore size) and ACS grade solvents. Melting points (mp’s) are
uncorrected. NMR spectra were recorded on either a 600 or 400 MHz
instrument. Peak locations were referenced using either TMS or residual
nondeuterated solvent as an internal standard. Proton coupling constants
are expressed in hertz. In some cases overlapping signals occurred in
the 13C NMR spectra. Spectroscopic data were in agreement with all
known intermediates 4 to 13.
2′,7-(Dibenzyloxy)-4′-(methoxymethyloxy)isoflav-3-ene (8). To a
suspension of 78g (5.03 g, 9.8 mmol) in anhydrous CH3CN (150 mL)
was added PPh3 ·HBr (3.36 g, 9.8 mmol) in five portions of ca. 0.7 g
each at intervals of ca. 15-20 min. By the last addition, the reaction
mixture became a clear solution. The progress of the reaction was
checked by TLC [CH2Cl2/MeOH (15:1)]. The reaction was complete
in 1-2 h. Solvents were then evaporated to dryness under vacuum at
rt to obtain an off-white residue. The crude material was used in the
next step without further purification.
To the solution of the crude material in anhydrous MeOH (ca. 400
mL) was added potassium tert-butoxide (2.2 g, 19.6 mmol) with stirring.
The reaction mixture was refluxed for ca. 18-24 h. Reaction progress
was monitored by TLC. After completion, the mixture was cooled to
rt and filtered. The precipitate was dissolved in CH2Cl2 (ca. 100 mL)
after washing with a small amount of cold MeOH (ca. 5-10 mL). The
organic layer was partitioned with water (ca. 50 mL), separated, and
dried over anhydrous Na2SO4. Solvents were evaporated to obtain 8
(3.3 g, 6.8 mmol) as an off-white solid in ca. 70% yield over the two
steps: mp 126-131 °C (lit.8g 115-118 °C); TLC Rf 0.39 [hexanes/
EtOAc (5:1)].
2′,7-Dibenzyloxy-4′-(tert-butyldimethylsilyloxy)isoflav-3-ene (10).
After addition of PPh3 ·HBr salt (0.74 g, 2.2 mmol) to a solution of 8
(1.0 g, 2.0 mmol) in anhydrous CH2Cl2 (10 mL), the reaction mixture
was allowed to stir at rt and followed by TLC [hexanes/EtOAc (2:1)].
The reaction was complete in 1-2 h, after which Et3N (0.5 mL, 3.6
mmol) followed by TBDMS-Cl (0.35 g, 2.3 mmol) were added. The
reaction was again monitored by TLC. After completion in ca. 12 h,
further toward completion, an aspect we also found to be useful
previously when going from isolated 12 to 13 via step j.8g
The final conversion of 13 to 1 (step l) was accomplished in a
manner analogous to how we previously effected this deprotection
to liberate 2 except that pyridine was utilized as the buffering system
rather than Et3N·3HF.8g The amorphous solids obtained after
evaporation of eluents from preparative TLC and column chroma-
tography, or after manipulating other types of solutions of the final
product, tend to entrain traces of solvent that are difficult to
completely remove by either drying or lyophilization. The integrity
of our final product was confirmed by melting point, optical rotation,
TLC, chiral HPLC, NMR (1H and 13C), HREIMS, and elemental
analysis. Because 1 readily can lose water to form the 6a-11a
double bond and can undergo oxidation to various other degradation
products, small portions of our final product were also forced in
each of these directions so as to provide fingerprints of such
materials for use during our chromatography studies. This informa-
tion is summarized in Tables 1 and 2 in the Supporting Information.
Experimental details for all new or significantly modified synthetic
procedures are provided below, namely, steps d, g, k, and l, along
with that for h, wherein we deployed the chiral catalyst that was
prepared in-house.
In summary, a 10-step total synthesis of glycinol from com-
mercially available starting materials is described. Providing product
having at least 98% ee in nearly 10% overall yield, this convenient
procedure can be used to supply quantities of material needed to
further characterize the promising SERM and other novel biological
properties of this distinct 6a-hydroxypterocarpan phytoalexin. Chiral
HPLC methods are also reported that can be used to provide ready
assessment of ee for the key enantiomeric intermediate 11, as well
as for the final product.
Experimental Section
General Experimental Procedures. Chemical reactions were
conducted under N2 in anhydrous solvents unless stated otherwise.
Reagents obtained from commercial suppliers were used without

2074 Journal of Natural Products, 2009, Vol. 72, No. 11
Notes
the reaction solvents were evaporated under vacuum at 30 °C. The
solid residue was dissolved in ca. 100 mL of CH2Cl2, and 15 g of silica
reagent17 (NaHSO4/SiO2) preactivated (120 °C for 48 h) was added.
The mixture was stirred vigorously for ca. 1 h. Solids were filtered,
and the filtrate was passed through a pad of silica (3 cm thick × 9 mm
dia.). The solvents were evaporated under vacuum, and the crude residue
was recrystallized from CH2Cl2/MeOH (1:5) to obtain 10 (0.77 g, 1.4
mmol) as white crystals in 70% yield: mp 104-106 °C [lit.,8g 106-107
°C]; TLC Rf 0.42 [hexanes/EtOAc (2:1)].
(+)-4′-tert-Butyldimethylsilyloxy-2′,7-(dibenzyloxy)isoflavan-3,4-
diol (11). A solution (2.5 mL) of OsO4 (0.25 g, 0.98 mmol) in toluene
was added to a solution of chiral ligand (DHQD)2PHAL (0.86 g, 1.1
mmol) in CH2Cl2 (5 mL). The mixture was stirred for ca. 1 h at -20
°C. A solution of 10 (0.48 g, 0.87 mmol) dissolved in CH2Cl2 (10 mL)
was then added slowly over 10-15 min, and the mixture stirred for
ca. 18 h at -20 °C. Reaction progress was monitored by TLC. After
completion, the reaction was allowed to warm to rt, and 15 mL of
10% sodium sulfite (pH ∼9.0) was added followed by 15 mL of 10%
sodium bisulfite (pH ∼4). The resulting deep brown mixture was
allowed to stir for ca. 2 h at rt, after which 10 mL of THF and 40 mL
of EtOAc were added.
The reaction mixture was stirred for 3-4 h at 55 °C (external oil
bath temp). After cooling, the mixture was filtered through a filter paper
and the filtrate passed through a pad of Celite (ca. 1 g). The pad was
washed with water (2 × 10 mL) and EtOAc (2 × 10 mL). The
combined organic phase was dried over anhydrous Na2SO4 and filtered.
The filtrate was applied to a quick silica pad filtration (1-2 cm thick
and 9 cm dia.), followed by evaporation of solvents under vacuum.
The crude product was purified using CC [silica gel ca. 60 g with
hexanes/EtOAc (3:1)] to obtain 11 (0.44 g, 0.75 mmol) as a white solid
in 86% yield and >98% ee: mp 75-77 °C; [R]25D +6.7 (c 1.6, MeOH);
TLC Rf 0.28 [hexanes/EtOAc (3:1)]; anal. (%) calcd for C35H40O6Si,
C 71.89, H 6.89, found C 71.83, H 6.92.
(-)-9-(-tert-Butyl dimethylsilyloxy)glycinol (13). Palladium on
carbon (10% Pd/C) (0.1 g, 20% w/w) was added to a dry ice/Me2CO-
bath chilled solution of 11 (0.5 g, 0.85 mmol) in anhydrous EtOH (ca.
10 mL). The mixture was set for hydrogenolysis at 35 psi at rt. The
reaction was followed by TLC and was complete in ca. 4 h. Prolonged
reaction times can cause reductions in overall yield. The reaction
mixture was passed through a pad of Celite and washed with EtOH (3
× 10 mL). The solvents were evaporated under vacuum to obtain 13
(0.28 g, 0.72 mmol) as an off-white powder in 85% yield: mp >170
°C; [R]25D -209.5 (c 0.3, MeOH); TLC Rf 0.41 [hexanes/CH2Cl2/MeOH
(10:10:1)]; anal. (%) calcd for C21H26O5Si, C 65.26, H 6.78, found C
65.75, H 6.76.
solid was lyophilized to obtain 1 (14 mg, 51 µmol) as a yellow
solid in ca. 78% yield: mp 108-112 °C; [R]25 -221.0 (c 0.3,
D
MeOH); TLC Rf 0.49 [hexanes/EtOAc (3:7)]; chiral HPLC retention
time 17.92 min (see Supporting Information, Table 1, for specific
9
1
details); H NMR ((CD3)2CO, 600 MHz) δ 8.55 (1H, s, Ar-OH),
8.47 (1H, s, Ar-OH), 7.30 (1H, d, J ) 9 Hz, H1), 7.20 (1H, d, J )
7.8 Hz, H7), 6.55 (1H, dd, J ) 8.4, 2.4 Hz, H2), 6.42 (1H, dd, J )
8.4, 2.4 Hz, H8), 6.31 (1H, d, J ) 2.4 Hz, H4), 6.24 (1H, d, J )
2.4 Hz, H10), 5.26 (1H, s, H11a), 4.95 (1H, s, 6a-OH), 4.11 (1H, d,
J ) 11.4 Hz, H6′), 4.02 (1H, d, J ) 11.4 Hz, H6); 13C NMR
(CD3OD, 150 MHz) δ 162.1, 161.1, 160.0, 157.3, 133.2, 125.1,
121.2, 113.0, 111.0, 109.2, 104.0, 98.9, 85.9, 77.2, 70.2; HREIMS
m/z calcd for C15H12O5 272.0685, found 272.0678; anal. (%) calcd
for C15H12O5 · 0.50H2O · 0.40CH3OH, C 62.90, H 5.00, found C 63.16,
H 5.38.
Acknowledgment. We are grateful to the U.S. Department of
Agriculture and the Southern Regional Research Center (New Orleans)
for their financial support.
Supporting Information Available: Chemical route and experi-
mental details for the synthesis of chiral catalyst; Table 1, having
chiral HPLC data and methods; Table 2, having physical properties
and structural data; and proton and carbon NMR spectra for racemic
and natural (-)-glycinol (1) syntheses. This material is available
free of charge via the Internet at http://pubs.acs.org.
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1
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NMR ((CD3)2CO, 600 MHz) δ 8.51 (1H, s, Ar-OH), 8.43 (1H, s, Ar-
OH), 7.29 (1H, d, J ) 9.0 Hz, H1), 7.19 (1H, d, J ) 8.4 Hz, H7), 6.54
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Journal of Natural Products, 2009, Vol. 72, No. 11 2075
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