An efficient method for the synthesis of enantiopure 2,3-anti-propionate aldols involving a 3,5-syn- or anti-diol subunit through chiral borane- mediated enantioselective aldol reaction coupled with radical reduction

Article abstract of DOI:10.1016/S0040-4039(00)00234-3

2,3-anti-Propionate aldols involving a 3,5-syn- or anti-diol subunit, versatile enantiopure segments available for macrolide synthesis, were prepared by a chiral oxazaborolidinone-promoted asymmetric aldol reaction with 2-bromo-1-ethoxy-2-methyl-1-trimethylsiloxyethene and the following highly anti-preferential radical debromination. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00234-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2633–2637
An efficient method for the synthesis of enantiopure
2,3-anti-propionate aldols involving a 3,5-syn- or anti-diol
subunit through chiral borane-mediated enantioselective aldol
reaction coupled with radical reduction
Syun-ichi Kiyooka ∗ and Kazi A. Shahid
Department of Chemistry, Faculty of Science, Kochi University, Akebono-cho, Kochi 780-8520, Japan
Received 11 January 2000; revised 2 February 2000; accepted 4 February 2000
Abstract
2,3-anti-Propionate aldols involving a 3,5-syn- or anti-diol subunit, versatile enantiopure segments available
for macrolide synthesis, were prepared by a chiral oxazaborolidinone-promoted asymmetric aldol reaction with
2-bromo-1-ethoxy-2-methyl-1-trimethylsiloxyethene and the following highly anti-preferential radical debromi-
nation. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: asymmetric aldol reaction; chiral borane; anti-propionate aldol; radical reduction.
There is currently a demand for an efficient means of preparing enantiopure 2,3-anti-propionate aldols
involving a 3,5-syn- or anti-diol which appear in the C16–C19 segment of scytophycin C,1 the C4–C7
segment of discodermolide,2 the C32–C35 subunit of the synthetic intermediate directed to rapamycin,3
the C20–C23 segment of ionomycin,4 which is shown as an example in Fig. 1, and so on.
We have previously reported that 1,3-syn- or anti-diol can be stereoselectively provided by applying a
chiral oxazaborolidinone (1 or 2)-promoted asymmetric aldol reaction to ketene silyl acetal 3.5 Further,
radical reduction of 2-bromo-3-hydroxy-2-methylpropionate derivatives with Bu3SnH was also reported
to give syn-propionate aldols via chelation control in the presence of MgBr2·OEt2.6 Guindon et al. have
already reported that the reverse anti-propionate aldols are surely obtained from the radical reduction
of the acetals of 2-methyl-2-phenylseleno-3,5-dihydroxypentanoate derivatives with Bu3SnH via non-
chelation control with respect to exocyclic effect.7 The above information persuaded us to investigate the
following reactions: after acetalization of the diols derived from successive aldol reactions of an aldehyde
with ketene silyl acetals, 3 and 4, the subunits above might be prepared by debromination according to
the radical reduction. We disclose herein a versatile solution toward the targets.
∗
Corresponding author. Fax +81 888 44 8360; e-mail: kiyo@cc.kochi-u.ac.jp (S. Kiyooka)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00234-3
tetl 16514

2634
Fig. 1. Synthetic targets as enantiopure subunit
A preliminary trial was done with the corresponding epimeric bromide 5. The bromide 5
was prepared by the chiral oxazaborolidinone-promoted asymmetric aldol reaction of 3-tert-
butyldimethylsiloxypropanal with 2-bromo-1-ethoxy-2-methyl-1-trimethylsiloxyethene 4 (74–75°C/15
mmHg; E:Z=1:2) in a stoichiometric amount of chiral borane 2 to give the α-bromo aldol in 92% yield
with >98% ee at C3, followed by treatment with 2,2-dimethoxypropane (88% yield). The bromide 5 was
then subjected to a hydrogen transfer reaction with Bu3SnH with a catalytic amount of Et3B in toluene
at −78°C with stirring overnight. Ethyl (2S,3S)-3,5-dihydroxy-3,5-isopropylidene-2-methylpentanoate
Scheme 1. aOne-pot reaction: (i) 10 min stirring; (ii) addition of excess 2,2-dimethoxypropane. bOne-pot reaction: (i) 20 min
stirring; (ii) evaporation of MeOH and addition of excess 2,2-dimethoxypropane with acetone

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11, [α]D22 +20.1 (c 1.49, CHCl3), was preferentially obtained in a ratio of 23:1 in 95% yield; the relative
anti configuration was confirmed on the basis of NMR experiments of its lactone derivative. The anti
selectivity has proved to be undoubtedly high in the α-bromo system bearing an isopropylidene acetal
moiety in the radical reductions.
The epimeric bromides 10a–d involving the enantiopure 1,3-diol unit required for the synthesis of
the targets under consideration were prepared as follows (Scheme 1). Reaction of isobutanal with
silyl nucleophile 3 smoothly proceeded in a stoichiometric amount of chiral borane 1 or 2 to afford
the corresponding dithiolane aldols in an essentially enantiopure state. The sequential procedure for
desulfurization was carried out under the conditions of Bu3SnH with AIBN,8 instead of Ni2B–H2,5a to
give the enantiopure aldols 7a,b in almost quantitative yields. TMS protection of the hydroxyl group
in 7a,b was achieved with TMSOTf and 2,6-lutidine, and the ethoxycarbonyl function in the resulting
TMS protected aldols was directly converted to the corresponding aldehydes to give 8a,b on treatment
of DIBAL at −78°C.
The second asymmetric aldol reaction of 8a,b, in this sequence to 10a–d, with silyl nucleophile 4 in
the presence of chiral borane 1 or 2 furnished aldol 9a–d (∼100% de at C3 and C5) in good yields. The
stereochemistry at the stereogenic center (C3) is completely controlled by only the stereochemistry of the
chiral borane used [‘promoter (catalyst) control’ on enantioselective acyclic stereoselection]5 so that each
3,5-syn or anti-diol unit is readily available in a pure state of relative configuration. After deprotection
Scheme 2. All reactions were performed at a substrate concentration of 0.1 M using 2.0 equiv. of Bu3SnH with a catalytic
amount of Et3B. aDiastereomeric ratio was determined from their 1H NMR spectra

2636
of the TMS function in 9a–d, subjecting the resulting diol to acetalization afforded 10a–d which are
epimeric only at C2.
The arranged epimeric bromides 10a–d underwent the debromination radical reaction under the
conditions of Bu3SnH and Et3B in toluene, similar to the reaction applied to 4, to afford the corresponding
target compounds 12a–d in high yields (86–92%) with excellent anti-diastereoselectivity (33–36:1), as
shown in Scheme 2. By using silica gel flash column chromatography, the target molecules were easily
24
purified to enantiopure 2,3-anti-propionate aldols involving a 3,5-syn- or anti-diol subunit:9,10 12a [α]D
24
24
−37.09 (c 0.62, CHCl3); 12b (the enantiomer of 12a) [α]D +37.0 (c 0.50, CHCl3); 12c [α]D −14.2
24
(c 0.42, CHCl3); and 12d (the enantiomer of 12c) [α]D −13.9 (c 0.62, CHCl3).
In conclusion, we have achieved an effective access to the preparation of essentially enantiopure
2,3-anti-propionate aldols involving a 3,5-syn- or anti-diol subunit, available for the enantioselective
synthesis of appropriate fragments of several complex macrolides, by using chiral oxazaborolidinone-
promoted asymmetric aldol reactions coupled with anti-diastereoselective radical reduction.
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Research (Grant No. 9554046 and 10640525)
from the Ministry of Education, Science, Culture and Sports.
References
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H.; Kira, H.; Hena, M. A.; Horiike, M. Tetrahedron Lett. 1997, 38, 3553–3556. (c) Kiyooka, S.-i.; Maeda, H. Tetrahedron:
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lactone derivatives.

2637
10. Selected spectroscopic data [1H NMR (CDCl3, 400 MHz) and 13C NMR (CDCl3, 100 MHz)]. Compound 11: 1H NMR δ
(ppm): 1.10 (d, J=7.07, 3H), 1.25 (t, J=7.07, 3H), 1.34 (s, 3H), 1.43 (s, 3H), 1.48 (m, 1H), 1.59 (ddd, J=5.64, 11.70, 11.96,
1H), 2.48 (dq, J=7.07, 7.84, 1H), 3.86 (ddd, J=1.72, 5.40, 11.72, 1H), 3.97 (dt, J=3.2, 11.68, 1H), 4.08 (ddd, J=2.72, 8.32,
11.24, 1H), 4.16 (dq, J=0.96, 7.07, 2H); 13C NMR δ (ppm): 12.27, 14.22, 19.06, 27.93, 29.67, 45.56, 59.72, 60.22, 70.59,
98.39, 174.66. Compound 12a: 1H NMR δ (ppm): 0.86 (d, J=6.84, 3H), 0.92 (d, J=6.76, 3H), 1.10 (d, J=7.07, 3H), 1.25 (t,
J=7.07, 3H), 1.29 (s, 3H), 1.30 (s, 3H), 1.52–1.69 (m, 3H), 2.48 (dq, J=7.07, 8.80, 1H), 3.41 (ddd, 6.56, 7.00, 9.52, 1H), 3.94
(ddd, J=5.52, 6.08, 9.48, 1H), 4.08–4.20 (m, 2H); 13C NMR δ (ppm): 12.47, 14.22, 17.58, 18.71, 24.10, 24.24, 32.91, 33.92,
45.59, 60.23, 68.46, 71.57, 100.48, 174.77. Compound 12c: 1H NMR δ (ppm): 0.77 (d, J=6.84, 3H), 0.81 (d, J=7.08, 3H),
1.01 (d, J=7.08, 3H), 1.15 (t, J=7.07, 3H), 1.24 (s, 3H), 1.29 (s, 3H), 1.50–1.61 (m, 3H), 2.48 (dq, J=7.07, 7.84, 1H), 3.40
(ddd, J=2.16, 6.60, 11.44, 1H), 3.90 (ddd, 2.44, 8.32, 11.48, 1H), 4.15 (q, J=7.07, 2H); 13C NMR δ (ppm): 12.32, 14.23,
17.66, 18.32, 19.59, 29.99, 30.13, 33.05, 45.61, 60.18, 70.90, 73.77, 98.37, 174.81.