Organocatalytic α-hydroxymethylation of cyclopentanone with aqueous formaldehyde: Easy access to chiral δ-lactones

Article abstract of DOI:10.1016/j.bmcl.2009.03.012

Optically active lactones are important synthons in perfume and aroma manufacturing. Therefore, developments of efficient asymmetric syntheses are desired. Organocatalytic asymmetric α-hydroxymethylations of cyclopentanone with aqueous formaldehyde have b

Full text of DOI:10.1016/j.bmcl.2009.03.012

Bioorganic & Medicinal Chemistry Letters 19 (2009) 3955–3958
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Organocatalytic
a-hydroxymethylation of cyclopentanone with aqueous
formaldehyde: Easy access to chiral d-lactones
Nobuyuki Mase, Azusa Inoue, Masaki Nishio, Kunihiko Takabe *
Department of Molecular Science, Faculty of Engineering, Shizuoka University, 3-5-1 Johoku, Hamamatsu 432-8561, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Optically active lactones are important synthons in perfume and aroma manufacturing. Therefore, devel-
Received 13 February 2009
Revised 3 March 2009
Accepted 4 March 2009
Available online 9 March 2009
opments of efficient asymmetric syntheses are desired. Organocatalytic asymmetric
tions of cyclopentanone with aqueous formaldehyde have been developed, to furnish the corresponding
-(hydroxymethyl)cyclopentanone with high enantioselectivity. Further chemical transformation of
hydroxymethyl)cyclopentanone gave the key intermediate for jasmine lactone, which is widely found
in fruits and flowers.
a-hydroxymethyla-
a
(
a-
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
Organocatalysis
Chiral lactone
Jasmine lactone
Aldol reaction
Chiral d-lactones as represented by jasmine lactone (1) are
widely found in fruits and flowers. Enantiomers of fragrances gen-
erally show characteristic differences in odor, therefore, the enan-
tiomeric composition is an important property of all living
organisms. Both enantiomers of the lactone 1 are found in nature.
is another useful tool for performing the direct
a-hydroxymethyla-
tion of ketones with aqueous formaldehyde, in which over 90%
6
,10
enantiomeric excess is achieved.
this pioneering work is a practical method for the preparation of
chiral -(hydroxymethyl)cyclohexanone, but has not yet been
To the best of our knowledge,
a
1
Interestingly (R)-lactone 1 is extracted from Jasminum flowers,
investigated for the synthesis of chiral cyclopentanone derivatives
whereas only (S)-enantiomer is biosynthesized in the Tuberose spe-
such as 4a. Our recent research focuses on organocatalytic aqueous
2
3
7
cies. Here we report the formal synthesis of both enantiomers of
through organocatalytic -hydroxymethylation of cyclopenta-
reactions, therefore we carefully reinvestigated the
a
-hydroxyme-
1
a
thylation of cyclopentanone (5a).
none with aqueous formaldehyde.
L
-Proline (7), which is one of the most effective organocatalytic
6
,10
The retrosynthesis of 1 is depicted in Scheme 1. Both enantio-
mers of 1 are available from the diol (S)-2.3a The diol is generated
from the d-hydroxymethyl lactone (S)-3 by employing a ring-open-
ing reaction. The chiral lactone (S)-3 is obtained by Baeyer–Villiger
reagents when employing a cyclohexanone donor,
catalyzed the
a
-hydroxymethylation of 5a. However, low yield and enantioselec-
tivities were observed with 5a in nonpolar solvent such as CH Cl
(y. 20%, 7% ee), and THF (y. 15%, 22% ee). On
2
2
(y. 23%, 24% ee), CHCl
3
oxidation of the chiral
a-(hydroxymethyl)cyclopentanone (S)-4a
prepared from cyclopentanone (5a). Although the final intermedi-
ate (S)-2 is synthesized in only three steps from cyclopentanone,
O
enantioselective
ing transformation. Prior to this Letter Baeyer–Villiger oxidations
of racemic -(hydroxymethyl)cyclopentanone 4a catalyzed by
engineered microorganisms were employed, but the chiral ketone
a was isolated in low enantiomeric excess (<12% ee).4
Recently, catalytic asymmetric -hydroxymethylation in an
a-hydroxymethylation of 5a is the most challeng-
O
OH
a
b
O∗
OH
EtO
a
(
S)-2
(
S or R)-1
4
a
O
O
O
aqueous solution of formaldehyde was intensively investigated.
Water-compatible transition metal-complexes catalyzed the
c
d
O
OH
OH
a
-hydroxymethylation of silicon enolates with aqueous formalde-
5
(S)-4a
5a
(S)-3
hyde, achieving excellent enantiofacial selectivity. Organocatalysis
Scheme 1. Retrosynthesis of (S)-jasmine lactone ((S)-1) from cyclopentanone (5a):
*
Corresponding author. Tel./fax: +81 53 478 1148.
E-mail address: tcktaka@ipc.shizuoka.ac.jp (K. Takabe).
(a) see Ref. 3a; (b) ring-opening reaction; (c) Baeyer–Villiger oxidation; (d)
hydroxymethylation.
a-
0
960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.03.012

3
956
N. Mase et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3955–3958
TBSO
SO Ph
H
N
C
N
+ TFA
13
10
H
21
Table 1
-Hydroxymethylation of cyclopentanone (5a) with aqueous formaldehyde (6) by use
of various organocatalysts
N
OH
O
a
N
H
N
N
H
2
N
H
a
N
H
C
10
H
21
HN
N
O
O
O
catalyst
30 mol%)
O
10
11
12
O
(
O
+
OH
H
H
O
OH
TBSO
O
CH Cl
2
2
OH
6
o
5
a
25 C, 48 h
(S)-4a
NH2
HO
OH
OH
OH
N
H
NH2
NH2
NH2
Yieldb (%)
eec,d (%)
Entry
Catalyst
1
4
15
16
17
1
2
3
4
7
10
11
12
13
14
15
16
14
3
2
12
10
5
22
ND
ND
ND
ND
45
Figure 1. Small amine molecules as organocatalyst.
e
5
the other hand, in polar solvent such as DMSO, DMF, MeOH, EtOH,
and 2-PrOH the diketone 8, derived through Mannich-type/Mi-
chael domino reaction, was obtained as a sole product with no dia-
stereoselectivity (Scheme 2).
Therefore, small amine molecules were screened as an organo-
catalyst as shown in Fig. 1 and Table 1. Well-known secondary
6
7
8
6
42
58
75
a
2 2
Conditions: small amine (30 mol %), 5a (5 equiv), and 6 (1.0 mmol) in CH Cl
(1.0 mL).
b
c
Determined by GC (TC-17) of the crude product.
Determined by chiral-phase HPLC analysis of its benzoate. HPLC (Daicel CHI-
8
9
amine molecules 10 and 11, which show high yields and enantio-
meric excess in organocatalytic aldol reactions, were ineffective in
RALCEL AD-H, hexane/2-PrOH = 97:3, flow rate 0.5 mL/min, k = 254 nm); t
(R), 38.13 (S) min.
R
= 32.06
d
aqueous
a
-hydroxymethylations (Table 1, entries 2 and 3). Due to
ND = not determined.
The reaction was carried out using 5a (1 equiv), 6 (10 equiv), and 13 (10 mol %)
e
the importance of efficient water-compatible organocatalytic reac-
tions special catalysts such as L-siloxyproline 12, diamine/TFA
combination catalyst 13, and tryptophan 14 have been devel-
10
in solvent-free condition.
7
11
oped and emerged in aqueous direct aldol reactions without the
addition of any organic solvents. Aqueous a-hydroxymethylations
ee and chemical yield of the solvents tested. Therefore, we chose
1
,4-dioxane as a solvent for further study (entry 14). Prolonged
reaction time improved chemical yield of 4a up to 60% (entry
5). Both enantiomers of threonine (16) are readily commercially
available, and they are generally less expensive than proline (7).
Under the same conditions, -threonine furnished the opposite
using these water-compatible catalysts were subsequently exam-
ined. The siloxyproline 12 and the diamine/TFA combination cata-
lyst 13 bearing long alkyl groups catalyzed the reaction to give the
aldol product 4 with slightly better yields (entries 4 and 5).
Although yield is very low, the simple primary amino acid trypto-
phan 14 showed better enantioselectivity than the secondary ami-
no acid proline 7 (entry 1 vs entry 6). Thus, we screened natural
1
D
enantiomer (R)-4a in 48% yield with 85% ee (entry 16).
Water molecules are essential in aldolase-catalyzed reactions
12
through proton relay, furthermore, in primary organocatalysis
primary amino acids in the
cyclopentanone (5a). We found that b-hydroxy amino acids such
as -serine (15) and -threonine (16) afforded high enantioselectiv-
ity (entries 7 and 8). In particular, -threonine (16) improved the
enantioselectivity as well as chemical yield (42% yield, 75% ee).
Using -threonine (16) as the primary catalyst, a series of differ-
a-hydroxymethylation reaction of
L
L
Table 2
a
-Hydroxymethylation of cyclopentanone (5a) with aqueous formaldehyde (6) by use
L
a
of L-threonine derivatives
L
O
16 or 17
30 mol%)
O
O
(
ent solvent systems were evaluated as shown in Table 2. Alcohols,
DMF, and DMSO were inferior solvents in terms of product yield
+
OH
H
H
solvent
6
o
(
entries 1, 4, and 6–8). Hexane, toluene, and diethyl ether were also
25 C, 48 h
5a
(S)-4a
poor solvents, probably due to low solubility of the catalyst 16 in
these solvents (entries 2, 3, and 5). The reaction in cyclopentanone
Entry
Catalyst
Solvent
Yieldb (%)
eec,d (%)
(
5a) without addition of any conventional organic co-solvent re-
sulted in good enantiomeric excess but low chemical yield (entry
). Halogenated solvent, acetonitrile, and THF afforded good ee in
1
2
3
4
5
6
7
8
9
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
ent-16
16
17
17
MeOH
Hexane
Toluene
DMF
2
5
7
7
8
ND
ND
ND
ND
ND
ND
ND
ND
75
73
75
71
76
9
moderate yield (entries 10–13). 1,4-Dioxane afforded the highest
2
Et O
EtOH
8
DMSO
2-PrOH
None
12
14
24
36
42
42
43
50
60
48
36
46
26
OH
N
H
O
10
11
12
13
14
CHCl
CH Cl
3
7
O
O
O
O
2
2
O
(
100 mol%)
MeCN
THF
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
+
OH
+
H
H
solvent
25 C, 48 h
82
76
6
o
e
5
a (5 eq)
(S)-4a
y. <23%, <24% ee)
8
15
(
(y. 0-74%)
16
ꢀ85
f
1
7
66
O
18
2
CH Cl
2
20
9
Mannich-type
Michael
19
1,4-Dioxane
a,b,c,d
See Table 1.
The reaction was carried out for 144 h.
The reaction was carried out using dry formaldehyde gas (excess) instead of
e
f
9
Scheme 2.
L-Proline (7) catalyzed
a
-hydroxymethylation of cyclopentanone (5a).
aqueous formaldehyde.

N. Mase et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3955–3958
3957
Table 3
O
O
a
-Hydroxymethylation of cycloalkanones (5) with aqueous formaldehyde (6) by use
m-CPBA
NaHCO
a
NaOEt
of L-threonine (16)
3
O
OH
CH
2
Cl
2
OH
EtOH
O
O
1
6
rt, 48 h
O
rt, 1 h
(S)-
4a
(
30 mol%)
(S)-3 (y. 82%)
OH
+
H
H
(
5
)n
1,4-dioxane
( )n
O
6
o
O
OH
25
C
ref 3a
(S)-4
OH
O∗
EtO
Entry
n
Time (h)
Yieldb (%)
eec (%)
(
S)-2 (y. 91%)
(
S or R)-1
1
2
3
4
1
2
3
4
48
48
96
96
50
63
31
47
82
93
97
93
Scheme 4. Formal synthesis of chiral jasmine lactone (1).
a,b,c
See Table 1.
Finally, we examined a formal synthesis of jasmine lactone (1)
as shown in Scheme 4. The ketone 4a (82% ee) was stereoselective-
ly oxidized with m-chloroperbenzoic acid to obtain the corre-
water significantly accelerated the aldol reaction.13 Aqueous form-
aldehyde is apparently more reactive and stereoselective than dry
formaldehyde gas (entry 17). To evaluate the influence of the hy-
1
9
sponding d-lactone (S)-3 in 82% yield. The d-lactone (S)-3 was
treated with sodium ethoxide in ethanol to afford the correspond-
ing diol (S)-2 in 91% yield, which is a precursor for both enantio-
mers of chiral jasmine lactone (1) via reported transformations.3
droxy moiety, tert-butyldimethylsilyl protected
L-threonine 17
a
was investigated in -hydroxymethylation. Chemical yields were
a
In summary,
enantioselectivity in this class of direct
cycloalkanones with aqueous formaldehyde. This method provides
direct access to chiral -(hydroxymethyl)cycloalkanone, which are
L
-threonine demonstrated good reactivity and
slightly low, but the enantioselectivity diminished (entries 18
and 19). This result suggested that a hydrogen bond is a key to
enhancing the reactivity as well as enantioselectivity.
Encouraged by these results, we further examined the scope of
this class of aldol reactions by utilizing a series of cycloalkanone
a-hydroxymethylation of
a
versatile precursors for chiral lactones.
donors 5 with
ditions (Table 3). Cyclohexanone (5b) was a good donor: the
reaction provided the -(hydroxymethyl)ketone (S)-4b in 63%
yield with 93% ee (entry 2). When cycloheptanone (5c) was used
as a donor, the expected -(hydroxymethyl)ketone 4c was ob-
tained with excellent enantioselectivity but low chemical yield
entry 3). The reaction of cyclooctanone (5d) donor afforded
-(hydroxymethyl)ketone 4d in moderate chemical yield with
L-threonine catalyst 16 under the same reaction con-
1
4
Acknowledgments
a
N.M. would like to thank professor Barbas for meeting an
opportunity to develop organocatalysis. We gratefully acknowl-
edge Dr. D.D. Steiner for a scientific discussion. This work was sup-
ported in part by a Grant-in-Aid for Scientific Research from Japan
Society for the Promotion of Science.
a
(
a
high enantiomeric excess (entry 4). Chemical yields of the desired
products 4 are not as high as desired, however; these are first
examples of preparing chiral five-, seven-, and eight-membered
References and notes
a
-(hydroxymethyl)cycloalkanones,15 which are potential chiral
1. Winter, M.; Malet, G.; Pfeiffer, M.; Demole, E. Helv. Chim. Acta 1962, 45, 1250.
2
3
.
.
Kaiser, R.; Lamparsky, D. Tetrahedron Lett. 1976, 17, 1659.
Synthesis of chiral Jasmine lactone: (a) Blaser, F.; Deschenaux, P. F.;
Kallimopoulos, T.; Jacot-Guillarmod, A. Helv. Chim. Acta 1991, 74, 787; (b)
Nohira, H.; Mizuguchi, K.; Murata, T.; Yazaki, Y.; Kanazawa, M.; Aoki, Y.;
Nohira, M. Heterocycles 2000, 52, 1359; (c) Sabitha, G.; Bhaskar, V.; Yadav, J. S.
Tetrahedron Lett. 2006, 47, 8179.
synthons in natural product synthesis.
The major -(hydroxymethyl)ketone 4a was determined to
a
have (S)-configuration by comparison with the reported optical
rotation value of d-lactone 3 and the diol (S)-2 derived from 4a
via Bayer–Villiger oxidation as described below.16 Therefore,
4.
Wang, S.; Chen, G.; Kayser, M. M.; Iwaki, H.; Lau, P. C. K.; Hasegawa, Y. Can. J.
Chem. 2002, 80, 613.
L-threonine catalyzed a re-facial attack on the enamine intermedi-
ate 19 (Scheme 3). This result is in accord with previously pro-
5. (a) Ozasa, N.; Wadamoto, M.; Ishihara, K.; Yamamoto, H. Synlett 2003, 2219; (b)
Ishikawa, S.; Hamada, T.; Manabe, K.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126,
-proline-based aldol transition states.6
,17,10
posed
that
mechanism, although the exact reason for stabilization is not
L
We propose
12236.
L-threonine catalyzed the aldol reaction with the following
6
7
8
.
.
.
(a) Casas, J.; Sundén, H.; Córdova, A. Tetrahedron Lett. 2004, 45, 6117; (b) Torii,
H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew. Chem., Int. Ed.
2004, 43, 1983.
1
8
clear. The iminium intermediate 18 derived from nucleophilic
addition of the catalyst 16 to the ketone 5a is stabilized by intra-
molecular hydrogen bonding. The stabilized iminium intermediate
(a) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F.,
III J. Am. Chem. Soc. 2006, 128, 734; (b) Mase, N.; Watanabe, K.; Yoda, H.;
Takabe, K.; Tanaka, F.; Barbas, C. F., III J. Am. Chem. Soc. 2006, 128, 4966.
Catalyst 10: (a) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H.
Angew. Chem., Int. Ed. 2004, 43, 1983; (b) Cobb, A. J. A.; Shaw, D. M.;
Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biomol. Chem. 2005, 3, 84; (c)
Hartikka, A.; Arvidsson, P. I. Tetrahedron: Asymmetry 2004, 15, 1831.
Catalyst 11: (a) Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.; Ley, S.
V. Org. Biomol. Chem. 2005, 3, 84; (b) Bernard, A. M.; Frongia, A.; Piras, P. P.;
Secci, F.; Spiga, M. Tetrahedron Lett. 2008, 49, 3037.
1
8 is tautomerized to the enamine intermediate, which reacts with
formaldehyde 6 through the transition state 19.
9
.
O
H
H
O
O
10. Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji, M. Angew.
H
Chem., Int. Ed. 2006, 45, 958.
11. Jiang, Z.; Liang, Z.; Wu, X.; Lu, Y. Chem. Commun. 2006, 2801.
12. Heine, A.; DeSantis, G.; Luz, J. G.; Mitchell, M.; Wong, C.-H.; Wilson, I. A. Science
O
H
5
a
H
N
O
6
+
N
O
O
(S)-4a
2001, 294, 369–374.
OH
O
OH
13. (a) Tanaka, F.; Thayumanavan, R.; Mase, N.; Barbas, C. F., III Tetrahedron Lett.
2004, 45, 325; (b) Amedjkouh, M. Tetrahedron: Asymmetry 2005, 16, 1411; (c)
Córdova, A.; Zou, W.; Ibrahem, I.; Reyes, E.; Engqvist, M.; Liao, W.-W. Chem.
Commun. 2005, 3586.
OH
18
H
H
NH2
14. Typical procedure for Table 3, entry 1: To the solution of cyclopentanone (5,
1
9
1
6
4
0
63
.3 mmol) was added. After stirring for 1 h at 25 °C, 37% aq formaldehyde
L, 1 mmol) was added. The reaction mixture was stirred for
l
L, 5 mmol) in dichloromethane (1.0 mL)
L-threonine (16, 36 mg,
Scheme 3. Proposed enamine mechanism and transition state.
solution (6, 75
l

3
958
N. Mase et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3955–3958
8 h, then purified by flash silica gel column chromatography without further
4
18. It has long been thought that a secondary enamine is better stabilized by
hyperconjugation, whereas a primary amine gives the predominant imine
form. However, recent advance on organocatalysis using primary amine,
effective tautomerization of the iminium form to the enamine form proceeded,
to construct carbon–carbon bond between the enamine and an acceptor
progressed in a stereoselective fashion. See: Xu, L.-W.; Lu, Y. Org. Biomol. Chem.
2008, 6, 2047.
19. The d-lactone (S)-3 is a highly versatile intermediate, for example, in Corey’s
synthesis of leukotriene B. See: Corey, E. J.; Pyne, S. G.; Su, W. G. Tetrahedron
Lett. 1983, 24, 4883.
workup to provide aldol product (4a, 57 mg, 0.5 mmol, 50% yield).
5. Reactions of cyclododecanone (12-membered) and/or cyclopentadecanone
1
1
1
(
15-membered) with aqueous formaldehyde in the presence of
L
-threonine
resulted in no reaction.
1
9
20
6. Compound (S)-3: ½
a
ꢁ
+28.0 (c 0.6, CHCl
ꢀ14.7 (c 2.0, EtOH), (lit. ½
3
), (lit. ½
a
ꢁ
+34.5 (c 0.6, CHCl
3
ꢀ14.1 (c 2.0, EtOH). Liu, Z.-
, 98% ee);
D
D
2
2
20
Compound (S)-2: ½
a
ꢁ
a
ꢁ
D
D
Y.; Ji, J.-X.; Li, B.-G. J. Chem. Soc., Perkin Trans. 1 2000, 3519.
7. (a) List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122, 2395; (b)
Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III J. Am. Chem. Soc. 2001, 123, 5260.