Glycolate aldol reactions with boron enolates of bis-4-methoxyphenyl dioxanone

Article abstract of DOI:10.1016/S0040-4039(02)00152-1

The boron enolate of 5S,6S-bis-5,6-(4-methoxyphenyl)-2-dioxanone reacted with various aldehydes to produce anti glycolate aldol products in high yield with good selectivity. The outcome is consistent with an E-enolate reacting through a closed transition state. The adducts were protected and the auxiliary was conveniently removed with ceric ammonium nitrate to give useful intermediates.

Full text of DOI:10.1016/S0040-4039(02)00152-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1789–1792
Glycolate aldol reactions with boron enolates of
bis-4-methoxyphenyl dioxanone
Merritt B. Andrus,* Kris G. Mendenhall, Erik L. Meredith and B. B. V. Soma Sekhar
Brigham Young University, Department of Chemistry and Biochemistry, C100 BNSN, Provo, UT 84602-5700, USA
Received 29 November 2001; accepted 11 January 2002
Abstract—The boron enolate of 5S,6S-bis-5,6-(4-methoxyphenyl)-2-dioxanone reacted with various aldehydes to produce anti
glycolate aldol products in high yield with good selectivity. The outcome is consistent with an E-enolate reacting through a closed
transition state. The adducts were protected and the auxiliary was conveniently removed with ceric ammonium nitrate to give
useful intermediates. © 2002 Elsevier Science Ltd. All rights reserved.
Aldol reactions with glycolate esters and aldehydes
have been used extensively to produce differentially
protected 1,2-diol products. Various auxiliary and lig-
and based approaches have been successful with pre-
formed enolates being the most common.1 While some
success has been found for anti stereoselection, the
majority of cases involve syn outcomes using oxazolidi-
none-based glycolates.2 A systematic study examining a
range of aldehydes with norephedrine glycolate esters
to produce syn products was recently reported by us.3
In contrast to stoichiometric approaches, catalytic gly-
colate aldols have been very limited with only a few
cases reported. Kobayashi’s tin glycolates with good
selectivity for either the syn or anti diols remain the
prime examples.4 Recently proline catalysis has been
extended to hydroxy-ketone aldol reactions with suc-
cess.5 The alternative approach using osmium-catalyzed
asymmetric dihydroxylation (AD) works very well for
syn diols from E olefins but is not useful for applica-
tions with Z-alkenes leading to anti diols.6 We recently
reported the use of 5,6-diphenyl-2-dioxanone 1 to pro-
duce anti products 2 with aldehydes under aldol condi-
tions (Scheme 1).7 The removal of the auxiliary was
limited to hydrogenation with palladium on carbon
catalysis. We now report the synthesis and aldol reac-
tivity of 5S,6S-bis-5,6-(4-methoxyphenyl)-2-dioxanone
that can now be easily removed under oxidative cleav-
age conditions to generate differentially protected diol
ester products.
The new dioxanone was made in analogous fashion to
the previous diphenyl substrate beginning with forma-
tion of E-4,4%-dimethoxy stilbene 6 (Scheme 2). 4-
Methoxybenzaldehyde was reacted with benzyl
phosphonate 5, obtained from an Arbuzov reaction
with ethyl phosphite, under basic conditions to give 6
as a single isomer in 93% yield as a white crystalline
solid (mp 211–214°C).8 Treatment with Sharpless’ AD-
mix-a reagent6 in a water-t-butyl alcohol mixture using
the standard conditions gave the S,S diol 7 in 84% yield
with 98% ee following recrystallization from ethyl ace-
tate–hexanes.9 The selectivity in this case was estab-
1
lished by H NMR of a mono Mosher’s ester formed
Scheme 1.
Keywords: aldol reaction; glycolate; enolate; diols; diastereoselection.
* Corresponding author. Tel.: (801) 378-8171; e-mail: mbandrus@
chemdept.byu.edu
Scheme 2.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00152-1

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M. B. Andrus et al. / Tetrahedron Letters 43 (2002) 1789–1792
from diol 7.10 Diol 7 was treated with di-n-butyl tin
oxide in benzene heated at reflux followed by addition
of t-butyl bromoacetate.11 The desired 5,6-bis-(4-
methoxyphenyl)-dioxanone 8 was obtained in 81% yield
following silica gel chromatography.12 Yields have
remained consistent for this three-step sequence on
scales of 5–10 g.
with the 5,6-diphenyldioxanone enoloate was found to
be somewhat lower with 8:1 selectivity.7a This new
bis-methoxyphenyl dioxanone has recently been used to
produce an advanced intermediated in the synthesis of
the ansamycin antibiotic geldanamycin.7b The b-
branched aldehyde for that case gave anti product with
15:1 selectivity. Cyclohexane carboxaldehyde in this
case gave product with reduced 7:1 selectivity (Table 1).
Aromatic aldehydes also showed reduced selectivity.
Benzaldehyde gave only 2:1 selectivity and cinnamalde-
hyde was moderate at 4:1. Other conditions using the
lithium enolate, generated from treatment with LDA,
or use of Lewis acids together with amine bases have
not been successful.
Aldol reactions were performed using optimized condi-
tions, which include triethylamine and dicyclohexyl-
boron triflate in methylene chloride at −78°C (Table
1).13 The boron enolate formation was allowed to occur
for a period of 3 h prior to addition of the aldehyde
that was used as 1.5 equivalents. After a reaction time
of 30 min, followed by standard quenching, work-up,
and purification, the aldol products were obtained in
good to excellent yields based on the auxiliary. The
observed ratios for the major anti isomers 9 and 10
The major S,S,S,S isomer was established previously
using single-crystal X-ray analysis.7a The origin for the
selectivity is a consequence of the aldehyde attack
occurring upon the re face of the enolate opposite from
the C-5 4-methoxyphenyl group (Scheme 3). With the
enolate locked in the E-configuration, the closed Zim-
merman–Traxler aldol transition state arrangement
generates anti aldol product with boron acting as Lewis
acid with the aldehyde in a 6-ring chair conformation.14
1
were determined by H NMR by integrating the well-
resolved signals corresponding to the protons located at
the a and b ester positions. Only trace amounts of syn
isomers were detected in a few cases. Normally, only
the two anti diastereomers were detected. The selectivity
was found to be excellent at 12:1 and 11:1 for alkyl
aldehydes including a- and b-branched examples indi-
cated. Previously the selectivity for isovaleraldehyde
The absolute stereochemistry was established previously
using X-ray analysis and direct comparison to products
prepared following independent procedures.7a Now
Table 1. anti aldol reactions with dioxanone 8
1
with the new aldol products, homonuclear H NMR
NOE measurements were made on the two anti product
isomers to confirm the stereochemistry (Scheme 4).
1
Irradiation of the H signals corresponding to the ben-
zylic lactone ring protons gave clear evidence for the
stereochemistry as observed previously. The major
S,S,S,S isomer showed a 5.4% enhancement for the
a-ester proton upon irradiation of the C-6 hydrogen,
indicating a cis relationship. In addition, a 6.3%
enhancement was seen at this position with the minor
S,S,R,R isomer upon C-5 irradiation.15
The advantage now offered by the bis-(4-
methoxyphenyl)-dioxanone auxiliary is ease of removal
using oxidative cleavage conditions in place of the
high-pressure hydrogenation conditions required previ-
ously. Three products 10 from Table 1 were trans-
Scheme 3.
Scheme 4.

M. B. Andrus et al. / Tetrahedron Letters 43 (2002) 1789–1792
1791
Table 2. Protection and auxiliary removal with aldol
adducts 9
2. syn Versions: (a) Evans, D. A.; Bender, S. L.; Morris, J.
J. Am. Chem. Soc. 1988, 110, 2506–2513; (b) Ku, T. W.;
Kondrad, K. H.; Gleason, J. G. J. Org. Chem. 1989, 54,
3487–3489; (c) Andrus, M. B.; Schreiber, S. L. J. Am.
Chem. Soc. 1993, 115, 10420–10421; (d) Evans, D. A.;
Barrow, J. C.; Leighton, J. L.; Robichaud, A. J.; Sefkow,
M. J. Am. Chem. Soc. 1994, 116, 12111–12112; (e) Crim-
mins, M. T.; Choy, A. L. J. Org. Chem. 1997, 62,
7548–7549; (f) Crimmins, M. T.; Choy, A. L. J. Am.
Chem. Soc. 1999, 121, 5653–5660; (g) Haight, D.; Birrell,
H. C.; Cantello, B. C. C.; Eggleston, D. S.; Haltiwanger,
R. C.; Hindley, R. M.; Ramaswany, A.; Stevens, N. C.
Tetrahedron: Asymmetry 1999, 10, 1353–1367. anti: (h)
Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.;
Stout, T. J. J. Am. Chem. Soc. 1990, 112, 7001–7011; (i)
Evans, D. A.; Gage, J. R.; Leighton, J. L.; Kim, A. S. J.
Org. Chem. 1992, 57, 1961–1963; (j) Evans, D. A.; Weber,
A. E. J. Am. Chem. Soc. 1986, 108, 6757–6761; (k) Li, Z.;
Wu, R.; Michalczyk, R.; Dunlap, R. B.; Odom, J. D.;
Silks, L. A., III J. Am. Chem. Soc. 2000, 122, 386–387.
3. Andrus, M. B.; Soma Sekhar, B. B. V.; Turner, T. M.;
Meredith, E. L. Tetrahedron Lett. 2001, 42, 7197–7201.
4. (a) Kobayashi, S.; Kawasuji, T. Tetrahedron Lett. 1994,
35, 3329–3332; (b) Kobayashi, S.; Hayashi, T. J. Org.
Chem. 1995, 60, 1098–1101; (c) Gennari, C.; Vulpetti, A.;
Pain, G. Tetrahedron 1997, 53, 5909–5914.
formed by protecting the b-hydroxyl with two groups,
either as a methyl ether using Meerwein’s salt or as a
tert-butyldimethylsilyl (TBS) ether (Table 2). The lac-
tone was then ring opened to the methyl ester 11 using
sodium methoxide (0.01 equiv.) in a 1:1 methanol–THF
mixture with stirring overnight. Ceric ammonium
nitrate (CAN, 2.5 equiv.) was then used in a 9:1 aceto-
nitrile–water mixture at 0°C for 2 h to cleave the
activated 4-methoxybenzyl ether generating hydroxy
ester product together with two equivalents of 4-
methoxybenzaldehyde. Chromatography then gave
pure differentially protected anti diol ester products in
good overall yield for the three-step sequence. Other
substrates and protecting groups are expected to give
similar results.
5. List, B.; Lerner, R. A.; Barbas, C. F. J. Am. Chem. Soc.
2000, 122, 2395–2396.
6. (a) Wang, L.; Sharpless, K. B. J. Am. Chem. Soc. 1992,
114, 7568–7569; (b) Kolb, H. C.; VanNieuwenhze, M. S.;
Sharpless, K. B. Chem. Rev. 1994, 94, 2483–2523.
7. (a) Andrus, M. B.; Soma Sekhar, B. B. V.; Meredith, E.
L.; Dalley, N. K. Org. Lett. 2000, 2, 3035–3037; (b)
Andrus, M. B.; Meredith, E. L.; Soma Sekhar, B. B. V.
Org. Lett. 2001, 3, 259–262. For other cyclic glycolate
aldol approaches, see: (c) Seebach, D.; Naef, R. Helv.
Chim. Acta 1981, 64, 2704–2709; (d) Pearson, W. H.;
Cheng, M.-C. J. Org. Chem. 1987, 52, 3176–3178; (e)
Comins, D. L.; Kuethe, J. T.; Lakner, F. J. J. Am. Chem.
Soc. 1999, 121, 2651–2652; (f) Evans, D. A.; Hu, E.;
Tedrow, J. S. Org. Lett. 2001, 3, 3133–3136; (g) Dixon,
D. J.; Ley, S. V.; Polara, A.; Sheppard, T. Org. Lett.
2001, 3, 3749–3752.
8. Preparation of trans-4,4%-dimethoxy-stilbene 6. Diethyl
4-methoxybenzylphosphonate 5 (10 g, 38.7 mmol) in
DMF (96.8 mL) was treated with NaOMe (6.27 g, 116
mmol) at rt for 20 min and p-anisaldehyde 4 (5.66 mL,
46.5 mmol) was added. The solution was allowed to stir
for an additional 30 min, then warmed to 100°C for 7 h.
The reaction was cooled to rt and stirred overnight then
the reaction was quenched with cold H2O. White crystals
were collected and washed with cold acetone (8.75 g, 93%
yield); mp 211–214°C; Rf=0.43 (30% EtOAc/hexanes);
1H NMR (300 Hz, CDCl3) l 7.44–7.41 (m, 4H), 6.93–
6.87 (m, 6H), 3.83 (s, 6H); 13C NMR (CDCl3) l 159.3,
130.7, 127.7, 126.4, 114.4, 100.3, 55.6; HRMS EI (M+Na)
calcd for C16H16O2 240.1150, found 240.1152.
The new 5S,6S-bis-5,6-(4-methoxyphenyl)-2-dioxanone,
readily made in two steps using catalytic AD-mix-a
reagent and a simple stilbene, produces anti glycolate
aldol products with a wide range of aldehydes. The
auxiliary is readily removed with CAN following pro-
tection to give synthetically useful anti diol intermedi-
ates. Efforts to further improve the selectivity and
apply the auxiliary to other transformations are
underway.
Acknowledgements
We wish to thank the National Institutes of Health
(GM57275) and the Brigham Young University Cancer
Center for funding and Dr. Bruce Jackson for mass
spectroscopy and Dr. Li Du for NMR assistance.
References
9. Mp 102–105°C, [h]D=−112 (c 1.50, CH2Cl2).
10. Mosher, H. S.; Dale, J. A. J. Org. Chem. 1970, 35,
4002–4008.
11. (a) Burke, S. D.; Sametz, G. M. Org. Lett. 1999, 1, 71–74;
(b) David, S.; Thieffry, A.; Veyrieres, A. J. Chem. Soc.,
Perkin Trans. 1 1981, 1796–1798.
1. (a) Gennari, C. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: New
York, 1991; Vol. 2, Chapter 2.4; (b) Cameron, J. C.;
Paterson, I. Org. React. 1997, 51, 1.

1792
M. B. Andrus et al. / Tetrahedron Letters 43 (2002) 1789–1792
12. See Ref. 7a for the procedure. Data for dioxanone 8: mp
116–118°C, [h]D=−125 (c 1.68, CH2Cl2); Rf=0.14 (30%
(113 mg, 86% yield); mp 106–108°C; [h]D=−132 (c 31.6,
CH2Cl2); Rf=0.20 (30% EtOAc/hexanes); H NMR (300
1
1
EtOAc/hexanes); H NMR (300 Hz, CDCl3) l 7.01–6.95
Hz, CDCl3) l 7.02–6.95 (m, 4H), 6.79–6.74 (m, 4H), 5.39
(d, J=9.3 Hz, 1H), 4.94 (d, J=9.0 Hz, 1H), 4.50 (d,
J=5.1 Hz, 1H), 4.25–4.17 (m, 1H), 3.75 (s, 6H), 2.83 (d,
J=5.1 Hz, 1H), 1.97–1.83 (m, 1H), 1.97–1.82 (m, 2H),
0.95 (t, J=7.1 Hz, 3H); 13C NMR (CDCl3) l 170.3,
160.2, 160.0, 129.0, 129.0, 128.2, 126.8, 114.0, 114.0, 85.2,
78.2, 77.2, 71.8, 55.4, 42.6, 24.5, 23.9, 21.7; HRMS FAB
(M+Na) calcd for C23H28O6Na 423.1784, found 423.1785.
Minor isomer 10 (3R,5S,6S)-[(R)-1-hydroxy-3-methyl-
butyl]-5,6-bis-(4-methoxyphenyl)-1,4-dioxan-2-one. White
solid; [h]D=−80.6 (c 5.06, CH2Cl2); Rf=0.16 (30%
(m, 4H), 6.81–6.76 (m, 6H), 5.42 (d, J=9.3 Hz, 1H), 4.76
(d, J=17.8 Hz, 1H), 4.60–4.54 (m, 2H), 3.78 (s, 6H); 13C
NMR (CDCl3) l 167.5, 160.2, 160.1, 128.9, 128.8, 127.4,
127.1, 114.0, 114.0, 86.4, 80.5, 66.5, 55.5.
13. General procedure: A solution of 8 (100 mg, 0.33 mmol)
in dry CH2Cl2 (15 mL) was cooled to −78°C under
nitrogen gas and triethylamine (0.12 mL, 0.87 mmol) was
added dropwise over 5 min. c-Hex2BOTf (1 M solution in
hexanes, 0.80 mL, 0.80 mmol) diluted in 1 mL dry
CH2Cl2 was added dropwise over 5 min. The solution
was allowed to stir at −78°C for 3 h. Aldehyde (0.50
mmol) was added dropwise over 5 min and the solution
was allowed to stir for 0.5 h. The solution was quenched
with a pH 7 buffer solution (2 mL), MeOH (0.4 mL), and
30% hydrogen peroxide (0.2 mL). The solution was
warmed to rt, diluted with ether (75 mL), and washed
with sat. NaHCO3 (5 mL). The aqueous phase was
extracted with ether (4×30 mL) and the organic layers
were washed with dilute HCl (10 mL) and brine (20 mL).
The organic layer was dried with MgSO4, concentrated
under vacuum, and silica gel radial chromatography gave
1
EtOAc/hexanes); H NMR (300 Hz, CDCl3) l 6.99–6.93
(m, 4H), 6.79–6.75 (m, 4H), 5.38 (d, J=9.6 Hz, 1H), 4.61
(d, J=9.3 Hz, 1H), 4.49 (d, J=4.5 Hz, 1H), 4.32–4.22
(m, 1H), 3.77 (s, 6H), 2.77 (d, J=6.3 Hz, 1H), 1.99–1.85
(m, 1H), 1.78–1.69 (m, 1H), 1.55–1.46 (m, 1H), 1.00–0.96
(dd, J=6.6, 5.4 Hz, 1H); 13C NMR (CDCl3) l 168.9,
160.2, 160.0, 128.8, 127.4, 126.8, 114.0, 114.0, 86.6, 80.5,
80.1, 71.1, 55.4, 41.7, 24.6, 23.9, 21.7; HRMS FAB
(M+Na) calcd for C23H28O6Na 423.1784, found 423.1765.
All other compounds were adequately characterized by
1H, 13C NMR and HRMS.
14. (a) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc.
1957, 79, 1920; (b) Fenzl, W.; Koster, R. J. Liebigs Ann.
Chem. 1975, 1322; (c) Masamune, S. Aldrichim. Acta
1978, 11, 23.
the desired aldol products as
a
mixture whose
diastereomeric ratio was determined by 1H NMR. Fur-
ther purification with a less polar eluent could be used to
furnish individual diastereomers. The following data
15. An X-ray structure was solved for an intermediate fol-
lowing the aldol reaction with this dioxanone in the route
to geldanamycin. See Ref. 7b.
from isovaleraldehyde is typical: major isomer
(3S,5S,6S)-[(S)-1-hydroxy-3-methylbutyl]-5,6-bis-(4-
methoxyphenyl)-1,4-dioxan-2-one. White crystalline solid
9