Preparation of new chiral building blocks: Highly enantioselective reduction of prochiral 1,3-cycloalkanediones possessing a methyl group and a protected hydroxymethyl group at their C2 position with Baker's yeast or CBS catalyst

Article abstract of DOI:10.1021/jo050349a

Highly enantioselective reduction of five-, six-, seven-, and eight-membered prochiral 1,3-cycloalkanediones possessing a methyl group and a protected hydroxymethyl group at their C2 position with baker's yeast or CBS catalyst and a new efficient and general method for preparing the 1,3-cycloalkanediones have been developed. These baker's yeast mediated reductions were found to produce corresponding ketols with high optical purity (> 99% ee) and high yield. All of the prepared ketols and their derivatives, chiral building blocks, have been fully characterized, and their absolute configurations have been determined. These compounds would be useful for the convergent synthesis of complex natural products.

Full text of DOI:10.1021/jo050349a

Preparation of New Chiral Building Blocks: Highly
Enantioselective Reduction of Prochiral 1,3-Cycloalkanediones
Possessing a Methyl Group and a Protected Hydroxymethyl Group
at Their C2 Position with Baker’s Yeast or CBS Catalyst
Hideaki Watanabe, Mitsuhiro Iwamoto, and Masahisa Nakada*
Department of Chemistry, School of Science and Engineering, Waseda University,
3-4-1, Ohkubo, Shinjuku, Tokyo 169-8555, Japan
mnakada@waseda.jp
Received February 24, 2005
Highly enantioselective reduction of five-, six-, seven-, and eight-membered prochiral 1,3-
cycloalkanediones possessing a methyl group and a protected hydroxymethyl group at their C2
position with baker’s yeast or CBS catalyst and a new efficient and general method for preparing
the 1,3-cycloalkanediones have been developed. These baker’s yeast mediated reductions were found
to produce corresponding ketols with high optical purity (>99% ee) and high yield. All of the prepared
ketols and their derivatives, chiral building blocks, have been fully characterized, and their absolute
configurations have been determined. These compounds would be useful for the convergent synthesis
of complex natural products.
Introduction
Actually, many chiral building blocks have been prepared
with baker’s yeast;3 however, some chiral building blocks
useful for natural product synthesis have been left
unprepared because preparation methods of their sub-
strates have never been developed.
We have reported highly enantioselective reduction of
2-benzyloxymethyl-2-methyl-1, 3-cyclohexanedione 1 with
baker’s yeast to produce 2 (yield 64%, >99% ee, Scheme
1).4 This new chiral building block has been utilized in
our synthetic studies on Taxol5a and convergent asym-
In the total synthesis of natural products, especially
terpenoids, construction of a stereogenic quaternary
carbon is often troublesome. One solution to avoid such
trouble is to use the chiral building blocks suitable for
the total synthesis of the target molecule; however, such
chiral building blocks are often hardly derived from
readily available compounds or natural products. Hence,
preparation of new chiral building blocks possessing a
stereogenic carbon via asymmetric reactions is very
important for the enantioselective total synthesis of
natural products.1
Since some enzyme-mediated reactions are readily
carried out, produce chiral compounds easily, and are
environmentally benign, preparation of chiral building
blocks with a biocatalyst has been extensively studied
and applied to asymmetric natural product synthesis.2
Baker’s yeast is widely utilized because of its avail-
ability, easy handling, and broad substrate allowance.
(2) For reviews of biocatalysis, see: (a) Santaniello, E.; Ferraboschi,
P.; Grisenti, P.; Msnzocchi, A. Chem. Rev. 1992, 92, 1071-1140. (b)
Robert, S. M. J. Chem. Soc., Perkin Trans. 1 1998, 157-169. (c) Robert,
S. M. J. Chem. Soc., Perkin Trans. 1 1999, 1-21. (d) Robert, S. M. J.
Chem. Soc., Perkin Trans. 1 2000, 611-633. (e) Robert, S. M. J. Chem.
Soc., Perkin Trans. 1 2001, 1475-1499. (f) Powell, K. A.; Ramer, S.
W.; del Cardayre´, S. B.; Stemmer, W. P. C.; Tobin, M. B.; Longchamp,
P. F.; Huisman, G. W. Angew. Chem., Int. Ed. 2001, 40, 3949-3959.
(g) Nakamura, K.; Yamanaka, R.; Matsuda, T.; Harada, T. Tetrahe-
dron: Asymmetry 2003, 14, 2659-2681.
(3) For reviews of baker’s yeast, see: (a) Servi, S. Synthesis 1990,
1-25. (b) Cusk, R.; Gla¨nzer, B. I. Chem. Rev. 1991, 91, 49-97. (c)
Hoegberg, H.-E.; Berglund, P.; Edlund, H.; Faegerhag, J.; Heden-
stroem, E.; Lundh, M.; Nordin, O.; Servi, S.; Voerde, C. Catal. Today
1994, 22 (3), 591-606. (d) Mochizuki, N.; Hiramatsu, S.; Sugai, T.;
Ohta, H.; Morita, H.; Itokawa, H. Biosci. Biotechnol. Biochem. 1995,
59 (12), 2282-2291. (e) Bertau, M.; Burli, M. Chimia 2000, 54 (9), 503-
507. Recently, Sugai and co-workers reported a new and efficient
strategy to prepare new chiral building blocks; see: (f) Fuhshuku, K.;
Tomita, M.; Sugai, T. Tetrahedron Lett. 2004, 45, 1763-1767.
* To whom correspondence should be addressed. Phone and Fax:
+813-5286-3240.
(1) We have also prepared the versatile chiral building blocks via
the catalytic asymmetric intramolecular cyclopropanation. See: (a)
Honma, M.; Sawada, T.; Fujisawa, Y.; Utsugi, M.; Watanabe, H.;
Umino, A.; Matsumura, T.; Hagihara, T.; Takano, M.; Nakada, M. J.
Am. Chem. Soc. 2003, 125, 2860-2861. (b) Honma, M.; Nakada, M.
Tetrahedron Lett. 2003, 44, 9007-9011.
10.1021/jo050349a CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/10/2005
4652
J. Org. Chem. 2005, 70, 4652-4658

Preparation of New Chiral Building Blocks
SCHEME 1. Baker’s Yeast Mediated Reduction of 1
SCHEME 2. Preparation of 1a
a Reagents and conditions: (a) LDA, HMPA, THF, -78 °C, 10
min, then MeI, -78 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)
2 N HCl, THF, 15 min, 95%.
metric total synthesis of allocyatin B2;5b however, five-,
seven-, and eight-membered carbocyclic congeners have
not been prepared.
Since many terpenoids have a polycyclic ring system
in their molecules as shown in Figure 1, chiral building
SCHEME 3. New Preparation of 1a
a Reagents and conditions: (a) cat. p-TsOH, HOCH2CH2OH,
CH(OEt)3, CH2Cl2, reflux; (b) cat. PdCl2 (CH3CN)2, benzene, reflux;
(c) O3, MeOH, -78 °C; NaBH4, rt; (d) NaH, BnBr, TBAI, THF/
DMF (10:1), rt; (e) THF/2N HCl (2:1), reflux, 64% (five steps).
FIGURE 1. Polycyclic terpenoids possessing a stereogenic
quaternary carbon.
catalyst, and a new effective and general preparation of
the prochiral 1,3-cycloalkanediones.
blocks convertible into their fragments would be benefi-
cial to their syntheses when they could be prepared.
Systematic studies on the baker’s yeast mediated
reduction of prochiral 2,2-disubstituted-1,3-cycloalkane-
diones have been reported by Brooks;6a,b however, no
results have been reported for substrates with two one-
carbon units at the C2 position. One reason for this
situation is that such substrates are hard to prepare;
actually, enolates of prochiral 1,3-cycloalkanediones pos-
sessing a substituent at their C2 position are easily
O-alkylated even with ethyl iodide.7
Although the baker’s yeast mediated reduction of
prochiral 2,2-disubstituted-1,3-cycloalkanediones pro-
duces a mixture of diastereomeric products in most cases,
the products are obtained with very high optical purity
and yield.6 Hence, the baker’s yeast mediated reduction
of prochiral 2,2-disubstituted-1,3-cycloalkanediones with
two one-carbon-units at its C2 position was surmised to
be a powerful protocol for preparing the chiral building
blocks when the diastereoselectivity is improved.
We have found that the baker’s yeast mediated reduc-
tion of 1 affords a single product with exceptionally high
diastereo- and enantioselectivity,4 so we decided to
investigate further the scope and generality of the baker’s
yeast mediated reduction of the congeners of 1, possess-
ing different ring sizes.
Results and Discussion
A New Preparation of 2-Benzyloxymethyl-2-
methyl-1,3-cyclohexanedione and Its Improved
Enantioselective Reduction with Baker’s Yeast. A
preparation of 1 reported previously4 is shown in Scheme
2. Compound 3 was prepared by Birch reduction of 2,6-
dimethoxybenzoic acid and subsequent methyl ester
formation.8 Then, 3 was methylated by MeI and LDA to
afford 4 (96%), followed by reduction with DIBAL-H
(96%) and benzylation (89%) to produce 5. Finally, acid-
catalyzed hydrolysis of the alkenyl ethers of 5 success-
fully afforded the desired 1,3-diketone 1 (95%).
This method is applicable only for the synthesis of 1
because other 2,2-disubstituted 1,3-cycloalkanediones
cannot be prepared via Birch reduction. Accordingly, we
started to develop a new general method for preparing
1, which is applicable to the preparation of other prochiral
1,3-cycloalkanediones possessing a methyl group and a
protected hydroxymethyl group at their C2 position.
Initial attempts to introduce a protected hydroxym-
ethyl group to the C2 position of 2-methyl-1,3-cyclohex-
anedione byalkylation proved fruitless because the O-
alkylated product formed exclusively. Hence, synthesis
of 1 was started from known compound 6 (Scheme 3).
Thus, 66b,9 was protected as bis-ketal 7, and the double
bond in 7 was successfully isomerized with the palladium
catalyst to afford thermodynamically more stable 8 as a
single isomer.10 Then, ozonolysis of 8, and the following
reductive workup with NaBH4, benzylation of the re-
sulted alcohol 9, and removal of the ketals under acidic
conditions gave 1 (64%, five steps). Since purification by
silica gel chromatography was unnecessary during this
We report herein highly enantioselective reduction of
prochiral 1,3-cycloalkanediones with two one-carbon-
units, a methyl group, and a protected hydroxymethyl
group at their C2 position, with baker’s yeast or CBS
(4) Iwamoto, M.; Kawada, H.; Tanaka, T.; Nakada, M. Tetrahedron
Lett. 2003, 44, 7239-7243. Our recent investigation improved the yield
of the product 2 to 90%.
(5) (a) Kawada, H.; Iwamoto, M.; Utsugi, M.; Miyano, M.; Nakada,
M. Org. Lett. 2004, 6, 4491-4494. (b) Takano, M.; Umino, A.; Nakada,
M. Org. Lett. 2004, 6, 4897-4900.
(6) (a) Brooks, D. W.; Mazdiyasni, H.; Sally, P. J. Org. Chem. 1985,
50, 3411-3414. (b) Brooks, D. W.; Mazdiyasni, H.; Grothaus, P. G. J.
Org. Chem. 1987, 52, 3223-3232. For extensive studies on the
prochiral 2,2-disubstituted-1,3-cyclohexanediones, see: (c) Fuhshuku,
K.-I.; Funa, N.; Akeboshi, T.; Ohta, H.; Hosomi, H.; Ohba, S.; Sugai,
T. J. Org. Chem. 2000, 65, 129-135. (d) Wei, Z.-L.; Li, Z.-Y.; Lin, G.-
Q. Synthesis 2000, 1673-1676.
(8) Tamai, Y.; Mizutani, Y.; Hagiwara, H.; Uda, H.; Harada, N. J.
Chem. Res., Synop. 1985, 148-149.
(9) Newman, M. S.; Manhart, J. H. J. Org. Chem. 1985, 50, 2113-
2114.
(10) Hosomi, A.; Sakurai, H. J. Am. Chem. Soc. 1977, 99, 1673-
(7) Mori, K.; Fujiwara, M. Tetrahedron 1988, 44, 343-354.
1675.
J. Org. Chem, Vol. 70, No. 12, 2005 4653

Watanabe et al.
SCHEME 6. Preparation of Acetonide 15a
SCHEME 4. Conversion of 1 to 10a
a Reagents and conditions: (a) baker’s yeast, 91% (93% conver-
sion), >99% ee; see the Supporting Information for the conditions;
(b) Me4NBH(OAc)3, AcOH, DMF, rt, 4 d, 83%.
a Reagents and conditions: (a) H2, Pd/C, MeOH, rt, 5 h, quant;
(b) acetone, cat. CSA, rt, 3 h, 65%.
SCHEME 7. Preparation of Acetonide 17a
SCHEME 5. Preparation of Crystalline 13a
a Reagents and conditions: (a) acetone, cat. CSA, rt, 2 h, 94%;
a 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%.
(b) Dess-Martin periodinane, CH2Cl2, rt, 1 h, 99%.
SCHEME 8. Preparation of Benzylidene Acetal 19a
synthesis except for the last step, this preparation
method is suitable for a large-scale preparation.
We found that the baker’s yeast reduction of 1 in the
presence of yeast extract improved the yield. Thus, 1
(140.0 mg, 0.57 mmol) was stirred with baker’s yeast (1.0
g, Oriental), 0.2% Triton X-100 in ethanol (0.3 mL),
sucrose (2.25 g), and yeast extract (0.1 g) in water (30
mL) at 30 °C. After 48 h, the reaction mixture was
worked up, and the crude product was purified by silica
gel chromatography to afford 2 (119.5 mg, 91% (93%
conversion), >99% ee). Although the reason has not been
clarified, addition of yeast extract certainly increased
yield of the baker’s yeast reduction of 1 because the
baker’s yeast reduction without yeast extract afforded 2
in 64% yield. Interestingly, no other product was obtained
in this reaction.
a 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%.
Although the (1S,3S)-configuration of 10 was expected
on the basis of Prelog’s rule,13 the absolute configuration
of 10 was unambiguously confirmed as described above.
However, the structure of 2 was still undetermined
because the possibility that the diol 10 had been obtained
from 2′ (Scheme 1) remained.14
Preparation of a crystalline derivative of 2 for X-ray
crystallographic analysis failed as mentioned above.
Furthermore, we were not able to elucidate the structure
of 2 by a comparison of NMR data between 2 and 2′ as
well as their NOE and NOESY experiments. Hence, the
structure of 2 was determined by comparing the deriva-
tive of 2 with the derivative of triol 11 because the
structure of 11 had been elucidated.
Product 2 was converted to some crystalline deriva-
tives; however, any crystals suitable for X-ray crystal-
lographic analysis were not prepared. Hence, the struc-
ture elucidation of 2 required several steps conversion
and the X-ray crystallographic analysis as described
below.
11
Reduction of ketone 2 with Me4NBH(OAc)3 afforded
10 exclusively (83%, >99% de) (Scheme 4), and the optical
purity of 10 (>99% ee) was determined by HPLC of its
bis-3,5-dinitrobenzoate. This result indicates that the
baker’s yeast reduction of 1 proceeds with high enantio-
selectivity (>99% ee).
As shown in Scheme 6, hydrogenolysis of 2 afforded
diol 14 (quant), and the reaction of 14 with acetone under
acidic condition gave acetonide 15 (65%). On the other
hand, 11 was transformed to acetonide 16 (94%) (Scheme
7), followed by Dess-Martin oxidation15 to generate
ketone 17 (99%). The structure of 17 was proved to be
different from that of 15 via spectroscopic analysis.
Then, as shown in Scheme 8, 16 was converted to
benzyl ether 18 (99%), followed by removal of acetonide
(92%), and subsequent benzylidene formation gave 19
As shown in Scheme 5, hydrogenolysis of 10 quanti-
tatively afforded triol 11, and formation of benzylidene
acetal produced 12 as a sole product (98%). Benzylidene
acetal 12 was transformed to crystalline p-bromobenzoate
13 (89%), and its whole structure was successfully
determined by X-ray crystallographic analysis.12 The
X-ray crystal structure clearly shows that relative con-
figuration of the two hydroxy groups is anti. Further-
more, 12 has a cis-fused bicyclic ring structure, suggest-
ing that the benzylidene acetal formed in a kinetically
controlled manner.
1
(quant) as a sole product. The H NMR, 13C NMR, IR,
[R]D, and mass spectral data of 19 are the same as those
(13) Prelog, V. Pure Appl. Chem. 1964, 9, 119-130.
(14) A yeast strain showing an opposite enantiotopic group selectiv-
ity toward similar cyclic diketones has been reported. See: Fuhshuku,
K.; Tomita, M.; Sugai, T. Adv. Synth. Catal. 2003, 345, 766-774.
(15) (a) Dess, D. E.; Martin, J. C. J. Org. Chem. 1991, 56, 7277-
7287. (b) Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem.
1999, 64, 4537-4538.
(11) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem.
Soc. 1988, 110, 3560-3578.
(12) See the Supporting Information.
4654 J. Org. Chem., Vol. 70, No. 12, 2005

Preparation of New Chiral Building Blocks
SCHEME 9. Preparation of 2-Benzyloxy-2-methyl-1,3-cyclopentanedione 24a
a Reagent and conditions: (a) cat. p-TsOH, HOCH2CH2OH, CH(OEt)3, CH2Cl2, reflux; (b) cat. PdCl2 (CH3CN)2, benzene, reflux,
(21/22 ) 1:26); (c) O3, MeOH, -78 °C; NaBH4, rt; (d) NaH, BnBr, TBAI, THF/DMF (10:1), rt; (e) THF/2 N HCl (2:1), reflux, 52% (five
steps).
TABLE 1. Enantioselective Reduction of 1 with (R)-CBS
SCHEME 10. Baker’s Yeast Mediated Reduction of
24a
Catalyst
(R)-CBS
(equiv)
concn
(L)
timea
(h)
yieldb
(%)
eec
(%)
entry
solvent.
1d,e
THF
CH2Cl2
CH2Cl2
0.10
0.10
0.15
0.04
0.04
0.15
2
2
10
64
72
91
24
>99
>99
a Reagents and conditions: (a) baker’s yeast, 25 (73%, >99%
ee), 26 (6%, >99% ee), 24 (18%); see the Supporting Information
for the conditions.
2f
3f
a Time required for the addition by a syringe pump. b Isolated
yield. c ee determined by HPLC. For HPLC conditions, see the
Supporting Information. d BH3‚THF (2.4 equiv) was used. e meso-
Diol (6.4%) was also obtained. f BH3‚SMe2 (2.4 equiv) was used.
added over 10 h, the yield of 10 was gratifyingly improved
to 91% (Table 1, entry 3). The absolute structure of 10
1
was confirmed by comparison of its H NMR, 13C NMR,
IR, [R]D, and mass spectral data with those of 10 prepared
as described in Scheme 4.
of the benzyl ether of structurally elucidated 12 (Scheme
5); hence, the absolute structure of 16 was confirmed as
shown in Scheme 7. From the results of the transforma-
tions shown in Schemes 4-7, the structure of 2 was
determined as shown in Scheme 1.
Reduction of 2 with Me4NBH(OAc)3 produced 10 with
high diastereoselectivity (>99% de) (Scheme 4); however,
this reduction proceeded sluggishly and required 4 days
to complete. Therefore, we investigated an alternative
method, selecting that using the CBS catalyst16 from
many enantioselective reduction methods because of its
wide applicability.
First, enantioselective reduction of 1 was examined
with BH3‚THF and (R)-CBS catalyst in THF (Table 1,
entry 1). A solution of 1 in THF was slowly added to a
mixture of BH3‚THF (2.4 equiv) in the presence of (R)-
CBS catalyst (0.1 equiv) in THF at 30 °C over 2 h by
means of a syringe pump. However, the optical purity of
10 obtained was unexpectedly low (24% ee, 64%), and
meso-diol (6.4%) was obtained as a byproduct.
After optimization of the conditions, we found the
optical purity of 10 dramatically increased to >99% ee
(72% yield) without generating meso-diols when the
reduction was carried out using CH2Cl2 and BH3‚SMe2
(Table 1, entry 2). Solvent effect on the enantioselectivity
of the oxazaborolidine reduction has been reported;16e,f
however, to the best of our knowledge, such a dramatic
improvement using CH2Cl2 as solvent has not been
reported. Finally, when a solution of 1 in CH2Cl2 was
Preparation and Enantioselective Reduction of
2-Benzyloxymethyl-2-methyl-1,3-cyclopentanedi-
one 24. Introduction of a protected hydroxymethyl group
to the C2 position of 2-methyl-1,3-cyclopentanedione by
alkylation afforded the O-alkylated product exclusively,
too. Hence, the synthesis of 24 was started from known
compound 20 according to the newly developed method
for 1 (Scheme 9). As a result, 24 was successfully
prepared from 20 (52%, five steps), revealing the wide
applicability of this new method. It should be noted that
purification by silica gel chromatography was again
unnecessary during this synthesis except for the last step.
Baker’s yeast mediated reduction of 24 was carried out
under the same conditions as those for 1, affording 25 in
73% yield along with its diastereomer 26 (6%) and the
recovered starting material 24 (18%) (Scheme 10). Optical
purity of 25 was difficult to determine by HPLC analysis;
hence, 25 was selectively reduced to 27 with Me4NBH-
(OAc)3 (93%, >99% de), and the ee of 27 was determined
successfully by HPLC analysis, indicating the ee of 27
was >99%. Reduction of 26 with Me4NH(OAc)3 similarly
afforded 27 (93%, >99% de). The absolute configuration
of 27 was proposed as shown in Scheme 11 because 27
was alternatively prepared from 24 with (R)-CBS cata-
lyst. The absolute configuration of 27 was in agreement
with Prelog’s rule, too; however, we decided to confirm
the absolute structure of 27 by X-ray crystallographic
analysis of its derivative.
We succeeded in preparing a single crystal of p-
bromobenzoate 29, which was obtained from 27 via 28
(88%, three steps, Scheme 11) by the same method as
that for preparing 13 in Scheme 5, and its whole
structure was gratifyingly determined by the X-ray
crystallographic analysis.12 However, the structure of 25
must be elucidated by further studies because the same
problem that arose in the structure determination of 2
remained; that is, regioselectivity of the reduction must
be determined. Oxidation of 28 afforded 30 (94%), and
(16) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc.
1987, 109, 5551-5553. (b) Mathre, D. J.; Jones, T. K.; Xavier, L. C.;
Blacklock, T. J.; Reamer, R. A.; Mohan, J. J.; Jones, E. T. T.; Hoogsteen,
K.; Baum, M. W.; Grabowski, E. J. J. J. Org. Chem. 1991, 56, 751-
762. (c) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37,
1986-2012. For enantioselective reduction of 2,2-disubstituted-1,3-
cyclopentanediones, see: (d) Shimizu, M.; Yamada, S.; Fujita, Y.;
Kobayashi, F. Tetrahedron: Asymmetry 2000, 11, 3883-3886. For
solvent effect in CBS catalysis, see: (e) Chan-Mo, Y.; Chunsan, K.;
Jae-Hong, K. Chem. Commun. 2004, 21, 2494-2495. (f) Nathan, J.
G.; Simon, J. Tetrahedron: Asymmetry 2003, 14 (15), 2115-2118.
J. Org. Chem, Vol. 70, No. 12, 2005 4655

Watanabe et al.
SCHEME 11. Transformations of 24-26 to 27-30a
SCHEME 13. Preparation of Bis-MTPA Ester 37a
a Reagents and conditions: (a) Dess-Martin periodinane, CH2Cl2,
rt, 92%; (b) TMSOTf, Et3N, CH2Cl2; Et2Zn, CH2I2, benzene, reflux;
FeCl3, DMF, 50 °C, 39%; (c) H2, Pd/C, MeOH, rt; (d) PivCl, Py,
CH2Cl2, rt, 79% (two steps); (e) BH3‚SMe2, (R)-CBS cat., CH2Cl2,
30 °C, 86%; (f) (S)-MTPACl, DMAP, CH2Cl2, rt, 76%.
Baker’s yeast mediated reduction of 32a and 32b
afforded 33a (91%, >99% ee) and 33b (95%, >99% ee)
as a sole product, respectively. Hydrogenation and the
following pivaloylation of 33a produced 33b (89%, two
steps), and optical purity of 33b was determined by
HPLC of its 3,5-dinitrobenzoate 33c; hence, optical
purities of 32a and 32b were determined as mentioned
above.
Since no derivatives of 33a and 33b crystallized, we
determined their absolute configuration based on Mosh-
er’s method.19 For this purpose, 33a and 33b were
transformed to their derivatives as shown in Schemes
12 and 13. While reduction of 33a and 33b with Me4-
NBH(OAc)3 afforded no product, CBS reduction of 32b
and 33b with the (R)-catalyst gave 34 in 84% and 86%
yields (>99% de), respectively.
a Reagents and conditions: (a) BH3‚SMe2, (R)-CBS cat., CH2Cl2,
30 °C, 91% (>99% ee); (b) Me4NH(OAc)3, AcOH, DMF, rt, quant,
(>99% de); (c) Me4NBH(OAc)3, AcOH, DMF, rt, 93%, (>99% de);
(d) H2, Raney-Ni, MeOH, rt; (e) PhCHO, cat. CSA, CH2Cl2, reflux,
97% (two steps); (f) p-BrBzCl, DMAP, CH2Cl2, rt, 91%; (g) DMP,
CH2Cl2, rt, 94%; (h) H2, Pd/C, MeOH, rt; (i) PhCHO, cat. CSA,
CH2Cl2, reflux, 97% (two steps).
SCHEME 12. Baker’s Yeast Mediated Reduction of
25a
On the other hand, since the structure of 12 had been
determined, 12 was transformed to 36. That is, 12 was
oxidized to the corresponding ketone by Dess-Martin
periodinane (92%), which was converted to the silyl enol
ether, followed by a ring-expansion reaction20 to generate
35 (36%, four steps) (Scheme 13). Enone 35 was trans-
formed to 36 by the hydrogenation accompanying hydro-
genolysis and the following selective pivaloylation (79%,
two steps). Compound 36 was converted to 34 by CBS
reduction with the (R)-catalyst (86%, >99% de), and all
the spectral data of 34 thus prepared was identical with
those of 34 prepared as described in Scheme 12; hence,
the absolute configuration of 34 was determined as
shown in Scheme 12. Furthermore, bis-(R)-MTPA ester
3719 was prepared from 34 with (S)-MTPACl (76%), and
Mosher’s method supported the absolute configuration
of 37 shown in Scheme 13 as well.
Since all of the spectral data of 36 proved that its
structure is nonidentical to that of 33b, the structure of
33b was elucidated as shown in Scheme 12. At the same
time, the structure of 33a was also elucidated as shown
in Scheme 12 because 33a was converted to 33b as shown
in Scheme 12. The absolute configuration of 33a and 33b
was also in agreement with Prelog’s rule.
a Reagents and conditions: (a) NaH, BnOCH2Cl, NaI, THF, 50
°C; 2 N HCl, 75% (25% conv); (b) NaH, PivOCH2I, THF, 50 °C; 2
N HCl, 86% (65% conv); (c) baker’s yeast, 91%, >99% ee; see the
Supporting Information for the conditions; (d) baker’s yeast, 95%,
>99% ee; (e) H2, Pd/C, MeOH, rt; (f) PivCl, Py, CH2Cl2, rt, 89%
(two steps); (g) 3,5-dinitrobenzoyl chloride, DMAP, CH2Cl2, rt, 87%;
(h) BH3‚SMe2, (R)-CBS cat., CH2Cl2, 30 °C, 84%, >99% ee; (i)
BH3‚SMe2, (R)-CBS cat., CH2Cl2, 30 °C, 86%, >99% ee.
two-step conversion of 25 as shown in Scheme 11 afforded
the same compound 30 (97%); hence, the structure of 25
was clearly elucidated as shown in Scheme 10.
Preparation and Enantioselective Reduction of
2-Benzyloxymethyl-2-methyl-1,3-cycloheptane-
dione, 2-Methyl-2-pivaloyloxymethyl-1,3-cyclohep-
tanedione, and 2-Methyl-2-pivaloyloxymethyl-1,3-
cyclooctanedione. Compounds 32a and 32b were pre-
pared by C-alkylation of 2-methyl-1, 3-cycloheptanedione
316a,17 as shown in Scheme 12. Alkylation using benzyl-
chloromethyl ether afforded the O-alkylated product as
its major product, but we found that use of iodomethyl
pivalate18 as the alkylating reagent increases the forma-
tion of the C-alkylated product. Although the O-alkylated
product was generated, it was hydrolyzed under the
acidic conditions in Scheme 12 to afford the starting
material 31.
Eight-membered 1,3-diketone 39 was also easily pre-
pared by the C-alkylation of 2-methyl-1,3-cyclooctanedi-
one 386a,17 (86% at 81% conversion) as shown in Scheme
14, and baker’s yeast mediated reduction of 39 afforded
40 as almost a sole product in 93% yield at 86%
conversion. The ee of 40 (>99% ee) was determined by
(19) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512-
(17) Lewicka-Piekut, S.; Okamura, W. H. Synth. Commun. 1980,
10, 415-20.
(18) Bodor, N.; Solan, K. B.; Kaminiski, J. J.; Shih, C.; Pogany, S.
J. J. Org. Chem. 1983, 48, 5280-5284.
519.
(20) Ito, Y.; Fujii, S.; Nakatsuka, M.; Kawamoto, F.; Saegusa, T.
Organic Syntheses; Wiley: New York, 1988; Collect. Vol. VI, pp 327-
333.
4656 J. Org. Chem., Vol. 70, No. 12, 2005

Preparation of New Chiral Building Blocks
SCHEME 14. Preparation of Bis-MTPA Ester 37a
a Reagents and conditions: (a) NaH, PivOCH2I, THF, 50 °C; 2 N HCl, 86% (81% conv); (b) baker’s yeast, 93% at 86% conversion, >99%
ee; see the Supporting Information for the conditions; (c) BH3‚SMe2, (R)-CBS cat., CH2Cl2, 30 °C, 73%, 88% ee; (d) for 41a: 3,5-dinitrobenzoyl
chloride, DMAP, CH2Cl2, rt, 92%; for 41b: (S)-MTPACl, DMAP, CH2Cl2, rt, 93%.
m), 2.36 (2H, d, J ) 7.3 Hz), 1.70-1.50 (6H, m), 1.15 (3H, s);
13C NMR (100 MHz, CDCl3) δ 137.7, 114.1, 113.0, 65.3, 63.8,
49.7, 35.0, 30.2, 18.6, 17.3; IR (KBr) νmax 2959, 2883, 1735,
1636, 1459, 1335, 1194, 1142, 1065 cm-1; HRMS(FAB) [M +
H]+ calcd for C14H23O4 255.1596, found 255.1587.
HPLC of the 3,5-dinitrobenzoate 41a, but unfortunately,
41a did not crystallize. Hence, (R)-MTPA ester 41b was
prepared from 40, and the absolute configuration of 41b
was determined by Mosher’s method as well as NOE
experiments (see the Supporting Information) on 40 and
41a, elucidating the absolute structure of 40 as shown
in Scheme 14.
Interestingly, CBS reduction of 39 with the (R)-CBS
catalyst afforded ketol 40 (73%) with rather low 88% ee.
This monoreduction would be rationally explained by the
transannular interaction, which is often observed in the
eight-membered ring system; that is, the first reduction
occurs smoothly, but the second reduction of 39 could be
very slow because formation of the product, the corre-
sponding diol, would suffer from the transannular inter-
action. Regioselectivity of the CBS reduction of 39 would
be explained by the steric factor; thus, the ketone was
reduced from the less hindered side. This was consistent
with the fact that reduction of 39 with NaBH4 afforded
racemic 40 preferentially (40/diastereomers ) 2.4:1, see
the Supporting Information).
In summary, highly enantioselective reduction of five-,
six-, seven-, and eight-membered prochiral 1, 3-cyclo-
alkanediketones possessing a methyl group and a pro-
tected hydroxymethyl group at their C2 position with
baker’s yeast, and a new efficient and general method
for preparing the 1,3-cycloalkanediketones have been
developed. These baker’s yeast mediated reductions were
found to produce corresponding ketols with high optical
purity (>99% ee) and high yield. In addition, a highly
enantioselective reduction of prochiral 1, 3-diketones to
the corresponding diol has been alternatively accom-
plished by use of the CBS catalysis. All of the chiral
building blocks reported herein would be useful for
enantioselective total synthesis of complex natural prod-
ucts, and such projects are now underway in our labora-
tory.
(E)-6-Methyl-6-(1-propenyl)-1, 4, 8, 11-tetraoxadispiro-
[4.1.4.3]tetradecane (8). To a solution of crude 7 (7.65 g, 30.1
mmol) in benzene (75 mL) was added PdCl2(CH3CN)2 (78.0
mg, 0.301 mmol), and the mixture was refluxed for 48 h. The
reaction mixture was filtered and evaporated to give crude 8
(7.65 g, 30.1 mmol). This crude 8 was used for the next step
without further purification: Rf ) 0.33 (hexane/ethyl acetate
1
) 3/1); mp 74.9-76.8 °C; H NMR (400 MHz, CDCl3) δ 5.82
(1H, dd, J ) 15.9, 1.5 Hz), 5.63 (2H, dq, J ) 15.9, 6.3 Hz),
4.00-3.83 (8H, m), 1.73 (3H, dd, J ) 6.3, 1.5 Hz), 1.72-1.58
(6H, m), 1.18 (3H, s); 13C NMR (100 MHz, CDCl3) δ 131.1,
126.2, 112.4, 65.1, 65.0, 52.4, 30.8, 18.9, 18.8, 15.1; IR (KBr)
νmax 2959, 2874, 1655, 1474, 1249, 1155, 1067, 1034 cm-1
;
HRMS(FAB) [M + H]+ calcd for C14H23O4 255.1596, found
255.1593.
(6-Methyl-1,4,8,11-tetraoxadispiro[4.1.4.3]tetradec-6-
yl)methanol (9). A solution of crude 8 (7.65 g, 30.1 mmol) in
methyl alcohol (250 mL) cooled to -78 °C was bubbled into
excess ozone for 4 h. N2 gas was bubbled into the reaction
mixture to purge ozone, and then to this reaction mixture was
added NaBH4 (2.41 g, 63.6 mmol) portionwise. After the
reaction mixture was warmed to room temperature, solvent
was removed under reduced pressure, and to the residue were
added EtOAc (100 mL) and saturated aqueous NH4Cl (100
mL). The aqueous layer was extracted with EtOAc (25 mL ×
2), and the combined organic layer was dried over Na2SO4,
filtered, and evaporated to give crude 9 (5.54 g, 22.7 mmol).
This crude 9 was used for the next step without further
purification: Rf ) 0.21 (hexane/ethyl acetate ) 1/1); mp 41.3-
43.7 °C, 1H NMR (400 MHz, CDCl3) δ 4.00-3.88 (8H, m), 3.79
(2H, d, J ) 5.4 Hz), 3.12 (1H, t, J ) 5.4 Hz), 1.68-1.52 (6H,
m), 1.07 (3H, s); 13C NMR (100 MHz, CDCl3) δ 112.9, 65.1,
64.9, 64.6, 50.5, 30.4, 18.8, 12.6; IR (KBr) νmax 3488, 2958, 2874,
1735, 1637, 1459, 1349, 1227, 1125, 1065, 953 cm-1; HRMS-
(FAB) [M + H]+ calcd for C12H21O5 245.1389, found 245.1397.
6-Benzyloxymethyl-6-methyl-1,4,8,11-tetraoxadispiro-
[4.1.4.3]tetradecane. To a suspension of NaH (60%, 998 mg,
24.9 mmol) and TBAI (838 mg, 2.27 mmol) in THF (50 mL)
was added a solution of crude 9 (5.54 g, 22.7 mmol) in THF
(10 mL × 1, 5 mL × 2) via a cannula at 0 °C. To this reaction
mixture was added a solution of benzyl bromide (2.83 mL, 23.8
mmol) in DMF (5 mL) at 0 °C, and the reaction mixture was
stirred at room temperature for 12 h. The reaction was
quenched with MeOH (0.2 mL). Saturated aqueous NH4Cl (100
mL) was added to the mixture, and the aqueous layer was
extracted with EtOAc (25 mL × 2). The combined organic layer
was dried over Na2SO4, filtered, and evaporated to give crude
6-benzyloxymethyl-6-methyl-1,4,8,11-tetraoxadispiro[4.1.4.3]-
tetradecane (7.60 g, 22.7 mmol): Rf ) 0.33 (hexane/ethyl
Experimental Section
6-Allyl-6-methyl-1,4,8,11-tetraoxadispiro[4.1.4.3]tetra-
decane (7). To a solution of 2-methyl-2-(3-propenyl)-1,3-
cyclohexadienone 6 (5 g, 30.1 mmol) in CH2Cl2 (100 mL) were
added p-toluenesulfonic acid (572 mg, 3.01 mmol), ethylene
glycol (15.1 mL, 271 mmol), and triethyl orthoformate (37.5
mL, 226 mmol), and the reaction mixture was refluxed for 24
h. The reaction mixture was quenched with saturated aqueous
NaHCO3 (50 mL) at ambient temperature and then extracted
with CH2Cl2 (25 mL × 2), and the combined organic layer was
dried over Na2SO4, filtered, and evaporated to give the crude
6 (7.65 g, 30.1 mmol). This crude 6 was sufficiently pure and
was used for the next step without further purification: Rf )
0.33 (hexane/ethyl acetate ) 3/1); mp 37.5-39.1 °C; 1H NMR
(400 MHz, CDCl3) δ 5.98 (1H, m), 4.91 (2H, m), 4.06-3.82 (8H,
1
acetate ) 3/1); H NMR (400 MHz, CDCl3) δ 7.37-7.22 (5H,
m), 4.52 (2H, s), 3.97-3.83 (8H, m), 3.64 (2H, s), 1.83 (2H, m),
1.70-1.53 (4H, m), 1.06 (3H, s); 13C NMR (100 MHz, CDCl3) δ
138.9, 128.0, 127.1, 127.0, 112.3, 73.4, 72.0, 65.1, 64.6, 50.9,
31.4, 18.7, 14.1; IR (neat) νmax 3428, 2964, 2892, 1712, 1560,
J. Org. Chem, Vol. 70, No. 12, 2005 4657

Watanabe et al.
1458, 1336, 1320, 1270, 1224, 1182, 1130, 1072, 1034 cm-1
;
(Na2SO4), and concentrated under reduced pressure. The
residue was purified by flash chromatography (hexane/ethyl
acetate ) 10/1 to 1/1) to afford 10 (3.5 mg, 83%, >99% de) as
a white solid.
HRMS(FAB) [M + H]+ calcd for C19H27O5 335.1858, found
335.1851.
2-Benzyloxymethyl-2-methylcyclohexane-1,3-dione (1).
To a solution of crude 6-benzyloxymethyl-6-methyl-1,4,8,11-
tetraoxadispiro[4.1.4.3]tetradecane obtained as above (7.60 g,
22.7 mmol) in THF (50 mL) was added 2 N HCl (25 mL), and
the reaction mixture was refluxed for 3 h. After the mixture
was cooled to room temperature, the aqueous layer was
extracted with EtOAc (125 mL × 2). The combined organic
layer was dried over Na2SO4, filtered, and evaporated. The
residue was purified by silica gel column chromatography
(hexane/ethyl acetate ) 6/1) to afford 1 (4.76 g, 64% (five
steps)) as a white solid: Rf ) 0.37 (hexane/ethyl acetate ) 3/1);
mp 52.0-52.4 °C; 1H NMR (400 MHz, CDCl3) δ 7.35-7.20 (m,
5H), 4.41 (s, 2H), 3.69 (s, 2H), 2.73-2.59 (m, 4H), 2.11-2.02
(m, 1H), 1.94-1.83 (m, 1H), 1.14 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 210.7, 137.4, 128.2, 127.5, 127.2, 76.2, 73.4, 63.5, 39.6,
17.7, 16.9; IR (KBr) νmax 3035, 2957, 2932, 2907, 2866, 1694,
1458 cm-1; HRMS(FAB) [M + H]+ calcd for C15H19O3 247.1334,
found 247.1331.
From 1 with CBS Catalyst. A solution of 1 (2.54 g, 10.3
mmol) in CH2Cl2 (100 mL) was added to a mixture of 0.5 N
(R)-CBS (3.09 mL, 1.55 mmol) and 90% BH3‚SMe2 (2.61 mL,
24.7 mmol) in CH2Cl2 (250 mL) via a syringe pump at 30 °C
over 10 h. The reaction was quenched with MeOH (5 mL), 2
N HCl (30 mL) was added to the reaction mixture, and then
the resulting solution was stirred for 10 h at room tempera-
ture. After dilution with Et2O (200 mL), the organic layer was
separated, washed with brine (250 mL), dried (Na2SO4), and
concentrated under reduced pressure. The residue was purified
by flash chromatography (hexane/ethyl acetate ) 10/1 to 1/1)
to afford 10 (2.30 g, 91%, >99% ee) as a white solid. The ee
was determined by HPLC (254 nm); Dicel Chiral Cell AS-H
0.46 cm i.d. × 25 cm; hexane/2-propanol ) 14/1; flow rate )
0.3 mL/min); retention time 37.5 min for (R,R)-10, 41.5 min
for (S,S)-10. Racemic 10 was prepared from 1 with dl-CBS
catalyst and was used as an authentic sample for HPLC: Rf
) 0.43 (hexane/ethyl acetate/CH2Cl2 ) 1/1/1); mp 76.5-77.8
°C (recrystalized by ethylmethyl ketone/hexane); 1H NMR (600
MHz, CDCl3) δ 7.36-7.28 (m, 5H), 4.59 (d, 1H, J ) 12.0 Hz),
4.53 (d, 1H, J ) 12.0 Hz), 4.15 (dd, 1H, J ) 11.2, 4.4 Hz), 3.80
(s, 1H), 3.68 (d, 1H, J ) 9.0 Hz), 3.56 (d, 1H, J ) 9.0 Hz), 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) δ
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; IR (KBr) νmax 2944, 1454,1047, 742 cm-1; HRMS-
(FAB) [M + H]+ calcd for C15H23O3 251.1647, found 251.1642;
(2R,3S)-2-Benzyloxymethyl-3-hydroxy-2-methylcyclo-
hexanone (2). A solution of sucrose (2.25 g), baker’s yeast
(1.00 g, Oriental Yeast Co.), and yeast extract (0.10 g) in H2O
(30 mL) was stirred at 30 °C, when brisk fermentation took
place. After 10 min, a solution of 1 (0.14 g, 0.57 mmol) in EtOH
(0.15 mL) and 0.2% Triton X-100 (0.3 mL) were added to the
reaction mixture. The mixture was stirred for 48 h at 30 °C.
Et2O (1.2 mL) and Celite (0.6 g) were then added to the
mixture, which was allowed to stand for 12 h. The mixture
was filtered through a pad of Celite, and the residue was
washed with ethyl acetate. The organic layer was separated,
washed with brine (10 mL), dried (Na2SO4), and concentrated
under reduced pressure. The residue was purified by flash
chromatography (hexane/ethyl acetate ) 20/1 to 10/1) to afford
of 2 (119.5 mg, 91% (93% conversion), >99% ee) as an oil: Rf
[R]22 +18.6 (c 1.0, CHCl3).
D
Acknowledgment. We thank the Material Charac-
terization Central Laboratory, Waseda University, for
technical support of the X-ray crystallographic analysis.
We also thank Professor Takeshi Sugai (Department of
Chemistry, Keio University) for helpful discussions
about baker’s yeast reduction. This work was financially
supported in part by the Uehara Memorial Foundation,
a Waseda University Grant for Special Research Projects,
and a Grant-in-Aid for Scientific Research on Priority
Areas (Creation of Biologically Functional Molecules
(No. 17035082)) from the Ministry of Education, Science,
Sports, Culture and Technology, Japan. We are also
indebted to 21COE “Practical Nano-Chemistry.”
1
) 0.52 (hexane/ethyl acetate/CH2Cl2 ) 1/1/1); H NMR (600
MHz, CDCl3) δ 7.36-7.28 (m, 5H), 4.56 (d, 1H, J ) 12.0 Hz),
4.53 (d, 1H, J ) 12.0 Hz), 3.98 (dd, 3.46, 1H, J ) 11.0 Hz),
3.78 (d, 1H, J ) 9.4 Hz), 3.72 (d, 1H, J ) 9.4 Hz), 3.50 (s, 1H),
2.50 (td, 1H,, J ) 13.8, 6.4 Hz), 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) δ 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; IR (thin film) νmax 2944, 1706, 740 cm-1
;
HRMS(FAB) [M + H]+ calcd for C15H23O3 249.1491, found
249.1490; [R]25 +33.8 (c 1.6, CHCl3).
D
(1S,3S)-2-Benzyloxymethyl-2-methylcyclohexane-1,3-
diol (10). From 2 with Me4NBH(OAc)3. A solution of 2 (4.2
mg, 1.7×10-2 mmol) in DMF (2 mL) was treated with Me4-
NHB(OAc)3 (0.201 g, 7.6×10-1 mmol) and AcOH (0.029 mL,
0.51 mmol) at room temperature. The reaction mixture was
stirred for 4 days. The reaction was quenched with saturated
NH4Cl (4 mL) at 0 °C. After dilution with Et2O (10 mL), the
organic layer was separated, washed with brine (10 mL), dried
Supporting Information Available: Synthesis and full
characterization of compounds in Scheme 2, 3, and 5-14; X-ray
crystal structures of 13 and 29 (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
JO050349A
4658 J. Org. Chem., Vol. 70, No. 12, 2005