Preparation of new chiral building blocks via asymmetric catalysis

Article abstract of DOI:10.1016/j.tetlet.2003.08.009

Highly enantio- and stereoselective preparation of some new chiral building blocks with baker's yeast or the CBS catalyst is described.

Full text of DOI:10.1016/j.tetlet.2003.08.009

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7239–7243
Preparation of new chiral building blocks via asymmetric
catalysis
Mitsuhiro Iwamoto, Hatsuo Kawada, Tomoyuki Tanaka and Masahisa Nakada*
Department of Chemistry, School of Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555,
Japan
Received 18 July 2003; revised 31 July 2003; accepted 6 August 2003
Abstract—Highly enantio- and stereoselective preparation of some new chiral building blocks with baker’s yeast or the CBS
catalyst is described.
© 2003 Elsevier Ltd. All rights reserved.
New chiral building blocks possessing an appropriate
carbon skeleton, stereogenic centers, and some func-
tional groups would contribute to a new and conver-
gent asymmetric total synthesis of natural products.
These compounds are not readily available, because
they are structurally different from naturally occurring
compounds, requiring multistep transformations from
easily accessible compounds. Hence, preparation of
such new chiral compounds via asymmetric synthesis is
very important.
In our laboratory, synthetic studies on some terpenoids
are now in progress, and one problem incurred in their
synthesis is the stereoselective construction of the chiral
quaternary carbon centers of the target molecule. As a
result of our retrosynthetic analysis of some terpenoids,
new chiral building blocks, 1a and 2b (Fig. 1) possess-
ing a chiral quaternary carbon center were found to be
useful for the convergent synthesis. Herein we report
highly enantio- and stereoselective preparation of some
new chiral building blocks with baker’s yeast or the
CBS catalyst.
Since 1a and 2b were surmised to be prepared from
meso-1,3-dione 3 by asymmetric reduction, we started
the asymmetric reduction of 3 by two methods, that is,
one is the method with baker’s yeast1 and the other is
the method with the CBS catalyst.2
Figure 1. Some new chiral intermediates and common pre-
curser 3.
Scheme 1.
Scheme 2. Reagents and conditions: (a) LDA, HMPA, THF,
−78°C, 10 min, then MeI, −78°C to 0°C, 1 h, 96%; (b)
DIBAL-H, CH2Cl2, −78°C, 15 min, 96%; (c) BnBr, NaH,
TBAI, THF, DMF, 10 h, 89%; (d) 2N HCl, THF, 15 min,
95%.
Keywords: asymmetric synthesis; baker’s yeast; CBS catalyst; enan-
tioselection; reduction.
* Corresponding author. Tel.: +81-3-5286-3240; fax: +81-3-5286-3240;
e-mail: mnakada@waseda.jp
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.009

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M. Iwamoto et al. / Tetrahedron Letters 44 (2003) 7239–7243
It has been reported that baker’s yeast reduction of 4
affords 5 with high enantioselectivity (Scheme 1, >99%
ee),3 hence, baker’s yeast reduction of 3 was surmised
to give good result. However, it was easily expected
that the product obtained by reduction of 3 would be a
complex mixture because 3 is a meso-1,3-diketone lack-
ing C2 symmetry, affording four stereoisomers. To our
surprise, baker’s yeast reduction of 3 has not been
reported. Hence, we started an investigation of the
stereoselectivity of the baker’s yeast reduction of 3.
A preparation of 3 is shown in Scheme 2. Compound 6
was prepared by the known method.4 Thus, Birch
reduction of 2,6-dimethoxybenzoic acid, followed by
methyl ester formation gave 6. Then, 6 was methylated
by MeI and LDA to afford 7 (96%), and 7 was reduced
by DIBAL-H (96%) and benzylated (89%) to give 8.
Finally, acid-catalyzed hydrolysis of the alkenyl ethers
of 8 successfully afforded the desired 1,3-diketone 3
(95%).
With the 1,3-diketone 3 in hand, baker’s yeast reduc-
tion of 3 was investigated. As shown in Scheme 3, the
reduction was carried out according to the reported
procedure.3a Thus, 3 (280.0 mg, 1.14 mmol) was stirred
with baker’s yeast (2.0 g), 0.2% Triton X-100 in ethanol
(0.6 ml), and sucrose (4.5 g) in water (60 ml) at 30°C.
After 48 h, the reaction mixture was worked up, and
the crude product was purified by silica gel chromat-
ography (hexane:ethyl acetate=20:1 to 10:1) to afford
1a (180.7 mg, 64%)5 and 3 (40.7 mg, 15%). No other
product was observed in this reaction. Ketone 1a was
highly diastereoselectively reduced with Me4NBH-
Scheme 3. Reagents and conditions: (a) baker’s yeast, sucrose,
Triton X, H2O, EtOH, 30°C, 48 h, 75% (at 85% conv., >99%
ee); (b) Me4NH(OAc)3, AcOH, DMF, rt, 4 d, 85%.
6
(OAc)3 to 2a (>99% de, 85%), and the optical purity of
2a (>99% ee) was determined by HPLC.7 This result
clearly shows that the baker’s yeast reduction of 3
proceeds with high stereoselectivity (>99% ee).
Next, the absolute structure of 1a was elucidated.
Though some crystalline derivatives were prepared
starting from 1a, p-bromobenzoate 10 was the only one
suitable for X-ray crystallographic analysis. Prepara-
tion of 10 is shown in Scheme 4. Thus, hydrogenolysis
of 2a quantitatively afforded triol 2b, and the reaction
of 2b with benzaldehyde and a catalytic amount of
CSA afforded benzylidene acetal 9 as the sole product
(98%). Acetal 9 was transformed to crystalline p-bro-
mobenzoate 10 (89%), and its whole structure was
determined by X-ray crystallographic analysis.8 The
X-ray crystal structure clearly shows that the absolute
structure of 10 is as shown in Figure 2, and the relative
configuration of the two hydroxy groups is anti. Fur-
thermore, 10 has a cis-fused bicyclic ring structure,
revealing that the benzylidene acetal formed in a kinet-
ically controlled manner.
Scheme 4. Reagents and conditions: (a) H2, Raney-Ni,
MeOH, rt, 10 h, quant.; (b) PhCHO, cat. CSA, CH2Cl2,
reflux, 10 h, 98%; (c) p-BrBzCl, DMAP, CH2Cl2, rt, 10 h,
89%.
Though the (S)-configuration of 1a was expected on the
basis of Prelog’s rule,9 the absolute configuration of 2a
was unambiguously confirmed as described above.
However, the absolute structure of 1a itself must be
determined because the above transformation can not
exclude another possibility that the diol 2a was
diastereoselectively obtained from 1a%.10 That is, it was
not determined which ketone in 3 is selectively reduced.
Since the preparation of a crystalline derivative from 1a
for X-ray crystallographic analysis was difficult as
stated above, the absolute structure of 1a was deter-
mined by the comparison of the derivative of 1a with
the compound derived from the structurally elucidated
triol 2b.
As shown in Scheme 5, a benzyl group of 1a was
removed by hydrogenolysis to give diol 1b (quant.),
followed by the reaction with acetone under acidic
condition to afford acetonide 11 (65%).11
Figure 2. X-Ray crystal structure of 10.

M. Iwamoto et al. / Tetrahedron Letters 44 (2003) 7239–7243
7241
mined by NMR technique. Hence, the structure of 12
must be elucidated as shown in Scheme 7. Thus, 12 was
converted to benzyl ether 14 (99%), followed by depro-
tection of the acetonide (92%), and benzylidene acetal
1
formation gave 15 (quant.). The H NMR, 13C NMR,
IR, [h]D, and mass spectral data of 15 are the same as
those of the benzyl ether of the structurally elucidated 9
(Scheme 4), determining the absolute structure of 12 as
shown in Scheme 6.
Scheme 5. Reagents and conditions: (a) H2, Pd/C, MeOH, rt,
5 h, quant.; (b) acetone, cat. CSA, rt, 3 h, 65%.
Since the absolute structure of 12 was elucidated, 12
was oxidized by Dess–Martin reagent12 to generate
ketone 13 (99%).13 The structure of 13 was found to be
apparently different from that of 11 as we expected. As
the result of transformations shown in Schemes 4–7, the
structure of 1a was proved as shown in Figure 1.
We successfully reduced 1a to 2a diastereoselectively
(>99% de) with Me4NBH(OAc)3 (Scheme 3). However,
this reduction proceeded sluggishly and required 4 days
to complete, so that we were prompted to investigate
another method to prepare 2a from 3. Among many
enantioselective reduction methods we selected the
method using the CBS catalyst2 because of its wide
applicability.
Scheme 6. Reagents and conditions: (a) acetone, cat. CSA, rt,
2 h, 94%; (b) DMP, CH2Cl2, rt, 1 h, 99%.
First, enantioselective reduction of 3 was examined
with BH3–THF and (R)-CBS catalyst in THF (entry 1,
Table 1). A solution of 3 in THF was slowly added to
a mixture of BH3–THF (2.4 equiv.) and (R)-CBS cata-
lyst (0.1 equiv.) in THF at 30°C over 2 h by means of
a syringe pump. However, the optical purity of 2a was
low (24% ee, 64%) and meso-diol (6.4%) was obtained
as a by-product.
Next, the solvent and the reducing reagent were
changed to CH2Cl2 and BH3–SMe2, respectively, and
the optical purity of 2a was dramatically increased to
>99% ee (72% yield) without generating meso-diols
(entry 2, Table 1). Finally, when a solution of 3 in
CH2Cl2 was added over a 10 h period, the yield of 2a
was successfully improved to 91% (entry 3, Table 1).
The absolute structure of 2a was confirmed as shown in
Scheme 7. Reagents and conditions: (a) BnBr, NaH, TBAI,
THF, DMF, 36 h, 99%; (b) p-TsOH, MeOH, 60°C, 6 h, 92%;
(c) PhCHO, cat. CSA, CH2Cl2, reflux, 10 h, quant.; (d) BnBr,
NaH, TBAI, THF, DMF, 15 h, 69%.
On the other hand, 2b was transformed to acetonide 12
(94%) (Scheme 6). This reaction gave 12 as the sole
product, but the structure of 12 was not clearly deter-
1
Figure 1 by comparison of its H NMR, 13C NMR, IR,
Table 1. Asymmetric reduction of 3 with (R)-CBS catalyst
Entry
Solv.
(R)-CBS (equiv.)
Conc. (mol/l)
Timea (h)
Yieldb (%)
Eec (%)
1d,e
2f
THF
CH2Cl2
CH2Cl2
0.10
0.10
0.15
0.04
0.04
0.15
2
2
10
64
72
91
24
>99
>99
3f
a Time required for the addition by a syringe pump.
b Isolated yield.
c Ee determined by HPLC. For HPLC conditions, see Ref. 7.
d BH3–THF (2.4 equiv.) was used.
e meso-Diol (6.4%) was also obtained.
f BH3–SMe2 (2.4 equiv.) was used.

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M. Iwamoto et al. / Tetrahedron Letters 44 (2003) 7239–7243
[h]D, and mass spectral data with those of 2a prepared
CDCl3): l 7.36–7.28 (m, 5H), 4.56 (d, J=12.0 Hz, 1H),
4.53 (d, J=12.0 Hz, 1H), 3.98 (dd, J=11.0, 3.46 Hz, 1H),
3.78 (d, J=9.4 Hz, 1H), 3.72 (d, J=9.4 Hz, 1H), 3.50 (s,
1H), 2.50 (dt, J=13.8, 6.4 Hz, 1H), 2.20 (m, 1H), 1.95
(m, 2H), 1.78 (m, 1H), 1.53 (m, 1H), 1.26 (s, 3H); 13C
NMR (125 MHz, CDCl3): l 212.9, 137.5, 128.5, 127.9,
127.6, 76.4, 75.8, 73.9, 54.1, 37.3, 28.5, 20.4, 14.8; HRMS
(FAB) [M+H]+ calcd for C15H23O3: 249.1491, found:
249.1458.
as described in Scheme 3.
In summary, highly enantioselective reduction of meso-
1,3-dione 3 with baker’s yeast, affording 1a (>99% ee),
was achieved. Also achieved is the subsequent highly
diastereoselective reduction of 1a with Me4NBH(OAc)3
generating 2a (>99% de) and the highly regioselective
acetal formation of 2b giving 9 and 12. A highly
enantioselective reduction of meso-1,3-dione 3 generat-
ing 2a directly (>99% ee) is alternatively realized by use
of the CBS catalyst.14,15 The absolute structure of all
products was unambiguously determined based on the
X-ray crystallographic analysis of 10 and the structure
interconversions as shown in Schemes 3–7. The new
chiral building blocks reported herein are useful for
asymmetric total synthesis of natural products, and
such projects are now underway in our laboratory.
6. Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am.
Chem. Soc. 1988, 110, 3560–3578.
7. 2a: a white solid; [h]3D2.1=+18.6 (c 1.0, CHCl3) (with CBS
catalyst), +18.5 (c 1.0, CHCl3) (with baker’s yeast); mp
76.5–77.8°C (ethyl acetate–hexane); IR (KBr): 2944,
1454, 1047, 742 cm−1 1H NMR (600 MHz, CDCl3): l
;
7.36–7.28 (m, 5H), 4.59 (d, J=12.0 Hz, 1H), 4.53 (d,
J=12.0 Hz, 1H), 4.15 (dd, J=11.2, 4.4 Hz, 1H), 3.80 (s,
1H), 3.68 (d, J=9.0 Hz, 1H), 3.56 (d, J=9.0 Hz, 1H),
3.34 (s, 1H), 1.89 (br, 1H), 1.89–1.72 (m, 2H), 1.66–1.60
(m, 2H), 1.58–1.43 (m, 3H), 0.86 (s, 3H); 13C NMR (125
MHz, CDCl3): l 137.6, 128.5, 127.9, 127.6, 77.3, 75.9,
73.7, 69.1, 43.0, 29.8, 28.4, 18.7, 14.4; HRMS (FAB)
[M+H]+ calcd for C15H23O3: 251.1647, found: 251.1642.
Ee was determined by HPLC (254 nm); Dicel Chiral Cell
AS-H 0.46 cm ƒ×25 cm; hexane/isopropanol=14/1; flow
rate=0.3 ml/min); retention time: 37.5 min for (R,R)-2a,
41.5 min for (S,S)-2a.
Acknowledgements
We thank Material Characterization Central Labora-
tory, Waseda University, for technical support of the
X-ray crystallographic analysis of 10. We also thank
Professor Takeshi Sugai (Department of Chemistry,
Keio University) for helpful discussion about baker’s
yeast reduction. This work was financially supported in
part by 21COE ‘Practical Nano-Chemistry’.
8. 10: a white solid; [h]2D5.2=+124.5 (c 1.0, CHCl3); mp
174.7–175.3°C (ethyl methyl ketone); IR (KBr): 2945,
2867, 1715, 1589, 1397, 1273, 1120, 1095, 1010, 759 cm−1
;
1H NMR (600 MHz, CDCl3): l 7.87 (d, J=8.7 Hz, 2H),
7.57 (d, J=8.7 Hz, 2H), 7.54–7.52 (m, 2H), 7.39–7.33 (m,
3H), 5.84 (dd, J=11.6, 4.85 Hz, 1H), 5.53 (s, 1H), 4.00
(d, J=11.8 Hz, 1H), 3.89 (t, J=2.8 Hz, 1H), 3.48 (d,
J=11.8 Hz, 1H), 2.16–2.13 (m, 1H), 1.98–1.91 (m, 1H),
1.81–1.78 (m, 2H), 1.69–1.61 (m, 2H), 1.03 (s, 3H); 13C
NMR (125 MHz, CDCl3): l 165.1, 138.4, 131.7, 131.0,
129.6, 129.0, 128.3, 127.9, 126.4, 102.2, 81.9, 72.8, 72.3,
36.6, 26.7, 26.6, 19.5, 14.5; HRMS (FAB) [M+H]+ calcd
for C22H24BrO4: 431.0858, found: 431.0859.
References
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1999, 3, 373–406; (b) Kayser, M.; Chen, G.; Stewart, J.
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H., Eds.; Springer-Verlag: Berlin, Germany, 2000; pp.
277–320; (f) Cusk, R.; Glanzer, B. I. In Stereoselective
Biocatalysis; Patel, R. N., Ed.; Marcel Dekker: New
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A. Trends Org. Chem. 2000, 8, 21–34.
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(b) For asymmetric reduction of 2-allyl-2-methyl-1,3-
cyclohexanedione, see: Brooks, D. W.; Mazdiyasni, H.;
Grothaus, P. G. J. Org. Chem. 1987, 52, 3223–3232. In
this baker’s yeast reduction, regioselectivity of the reduc-
tion was low.
4. Tamai, Y.; Mizutani, Y.; Hagiwara, H.; Uda, H.;
Harada, N. J. Chem. Res. Synop. 1985, 148–149.
5. 1a: a colorless viscous oil; [h]2D5.2=+33.8 (c 1.6, CHCl3);
IR (thin film): 2944, 1706, 740 cm−1; 1H NMR (600 MHz,
9. Prelog, V. Pure Appl. Chem. 1964, 9, 119–130.
10. The yeast strain showing an oppsite enantiotopic-group
selectivity toward similar cyclic diketones has been
reported, see: Fuhshuku, K.; Tomita, M.; Sugai, T. Adv.
Synth. Catal. 2003, 345, 766–774.
11. 11: a white solid; [h]2D3.0=+70.8 (c 1.0, CHCl3); mp 49.5–
1
50.8°C; IR (KBr): 2960, 1703, 1196, 1064 cm−1; H NMR
(600 MHz, CDCl3): l 4.03 (d, J=11.9 Hz, 1H), 3.87 (dd,
J=11.6, 4.03 Hz, 1H), 3.69 (d, J=11.9 Hz, 1H), 2.62 (dt,
J=11.7, 7.3 Hz, 1H), 2.20–2.16 (m, 1H), 2.05–2.00 (m,
1H), 1.91–1.84 (m, 1H), 1.77–1.74 (m, 1H), 1.66–1.58 (m,
1H), 1.43 (2s, 6H), 1.37 (s, 3H); 13C NMR (125 MHz,
CDCl3): l 212.9, 99.3, 74.1, 66.6, 48.8, 36.9, 29.6, 25.5,
20.9, 18.9, 15.2; HRMS (FAB) [M+H]+ calcd for
C11H19O3: 199.1334, found: 199.1349. Benzylidene group
was not selected for the protection because a new stereo-
genic center forms in the product, rendering the structure
elucidation difficult.
12. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1991, 113,
7277–7287; (b) Frigerio, M.; Santagostino, M.; Sputore,
S. J. Org. Chem. 1999, 64, 4537–4538.
13. 13: a white solid; [h]2D3.0=−62.8 (c 1.0, CHCl3); mp 38.3–
1
39.0°C; IR (KBr): 2954, 1710, 1203, 1091 cm−1; H NMR

M. Iwamoto et al. / Tetrahedron Letters 44 (2003) 7239–7243
7243
(600 MHz, CDCl3) l 4.31 (d, J=11.7 Hz, 1H), 4.17 (t,
J=2.8 Hz, 1H), 3.38 (d, J=11.7 Hz, 1H), 2.49–2.43 (m,
1H), 2.41–2.37 (m, 1H), 2.22–2.14 (m, 1H), 2.08–2.02 (m,
1H), 1.86–1.79 (m, 2H), 1.44 (s, 3H), 1.43 (s, 3H), 1.34 (s,
3H), 1.00 (s, 3H); 13C NMR (125 MHz, CDCl3): l 212.1,
98.4, 74.7, 64.2, 46.8, 37.7, 29.3, 26.3, 20.4, 19.0, 18.7;
HRMS (FAB) [M+H]+ calcd for C11H19O3: 199.1334,
found: 199.1311.
14. For enantioselective reduction of 2,2-disubstituted-1,3-
cyclopentanediones, see: Shimizu, M.; Yamada, S.;
Fujita, Y.; Kobayashi, F. Tetrahedron: Asymmetry 2000,
11, 3883–3886.
15. Additives that slow down the second reduction of meso-
diketone 3 were not investigated. For such additives, see
Ref. 14 and references cited therein.