Organocatalytic enantioselective synthesis of secondary α-hydroxycarboxylates

Article abstract of DOI:10.1055/s-2007-982552

Enantioenriched secondary α-hydroxycarboxylates have been synthesized in good yields and enantioselectivities by using the cross-aldol reaction of ketones and ethyl glyoxylate with a proline-derived dipeptide as the catalyst. Georg Thieme Verlag Stuttgart

Full text of DOI:10.1055/s-2007-982552

LETTER
1605
Organocatalytic Enantioselective Synthesis of Secondary a-Hydroxy-
carboxylates
Enantioselective
a
o
j
f
Secon
a
dary
a
-Hy
s
droxycarb
e
oxylate
s
khar Dodda, Cong-Gui Zhao*
Department of Chemistry, University of Texas at San Antonio, One UTSA Circle, San Antonio, Texas 78249-0698, USA
E-mail: cong.zhao@utsa.edu
Received 8 February 2007
a-hydroxyphosphonates from a-formylphosphonate hy-
drates,11c we envisioned that enantioenriched secondary
a-hydroxycarboxylates should be accessible from the di-
rect aldol reaction of glyoxylates (a-formylcarboxylates)
and ketones. Herein we wish to report our preliminary
results on the enantioselective synthesis of secondary a-
hydroxycarboxylates from a direct aldol reaction of
ketones and ethyl glyoxylate by using an L-proline-de-
rived dipeptide as the catalyst.
On account of our earlier study,11a–c some readily avail-
able L-proline derivatives (Figure 1) were chosen as the
catalysts. With the exception of catalyst 5, these catalysts
are either commercially available products (1, 2) or
known compounds (3, 4); the latter were synthesized
according to the reported methods.7f,12 The synthesis of
the new catalyst 5 is shown in Scheme 1. The coupling of
Cbz-protected (R)-4-hydroxy-L-proline (6)13 and L-valine
benzyl ester·HCl (7) in the presence of EDCI/HOBt led to
the protected dipeptide derivative 8 in 86% yield. Acety-
lation of 8 with acetyl chloride in the presence of pyridine
followed by hydrogenation under standard conditions
gave the desired catalyst 5 in almost quantitative yield.
Abstract: Enantioenriched secondary a-hydroxycarboxylates have
been synthesized in good yields and enantioselectivities by using
the cross-aldol reaction of ketones and ethyl glyoxylate with a
proline-derived dipeptide as the catalyst.
Key words: aldol reaction, enantioselectivity, organocatalysis,
ethyl glyoxylate, ketones, a-hydroxycarboxylate
Secondary a-hydroxycarboxylic acids and their alkyl
esters are very useful intermediates in the synthesis of
many bioactive natural products.1 Owing to their synthetic
relevance, several asymmetric methods have been devel-
oped for the synthesis of these compounds in enantio-
enriched forms. For example, enantioenriched secondary
a-hydroxycarboxylates have been synthesized through
the asymmetric reduction of a-ketoesters, with either
chiral metal complexes,2 or chiral auxilaries,3 or en-
zymes.4 These compounds have also been synthesized
through the addition of a nucleophilic reagent to glyoxy-
lates in the presence of chiral metal complexes.5 Alterna-
tively, they may be obtained through the enzymatic
resolution of racemic a-hydroxycarboxylates.6
Since List and Barbas III published their seminal work on
the L-proline-catalyzed asymmetric cross-aldol reaction
of aldehydes and ketones,7 many new L-proline deriva-
tives have been prepared and extensively studied as orga-
nocatalysts in the asymmetric cross-aldol reactions.8
There are also a few examples where these organocata-
lysts are used for the enantioselective synthesis of a-hy-
droxycarboxylic acid derivatives.9,10 For example, Gong
and co-worker reported that a bifunctional prolinamide
derivative is a good catalyst for the asymmetric synthesis
of a-hydroxycarboxylic acids.9 Nevertheless, all the re-
ported methods can only produce tertiary a-hydroxy-
carboxylates.9,10 To the best of our knowledge, there is no
general organocatalyzed aldol approach for the enantio-
selective synthesis of secondary a-hydroxycarboxylates.
Recently, we and others have demonstrated9–11 that L-pro-
line derivatives are very efficient catalysts for the cross
aldol reaction of ketones and activated carbonyl com-
pounds, such as, 1,2-diketones,11a a-ketophosphonates,11b
and a-formylphosphonate hydrates.11c During the
research on the enantioselective synthesis of secondary
R1
O
COR
N
H
N
H
HN
CO2R2
1 R = NH2
2 R = OH
3 R1 = R2 = H
4 R1 = H; R2 = Me
5 R1 = OAc; R2 = H
Figure 1 Catalysts screened for the cross-aldol reaction
HO
i
H2N
·HCl
CO2Bn
CO2H
N
Cbz
6
7
HO
AcO
O
O
ii, iii
N
N
H
Cbz
HN
HN
CO2Bn
CO2H
8
5
SYNLETT 2007, No. 10, pp 1605–1609
Advanced online publication: 07.06.2007
DOI: 10.1055/s-2007-982552; Art ID: S00807ST
© Georg Thieme Verlag Stuttgart · New York
1
8
.0
6
.2
0
0
7
Scheme 1 Synthesis of catalyst 5. Reagents and conditions:
(i) EDCI, HOBt, NMP, CH2Cl2, 86%; (ii) AcCl, pyridine, CH2Cl2,

1606
R. Dodda, C.-G. Zhao
LETTER
Table 1 Catalyst Screening and Reaction Conditions Optimizationa
O
OH
O
O
1–5
CO2R
H
CO2R
9a
10a (R = Et)
10a' (R = Me)
10a'' (R = t-Bu)
11a (R = Et)
11a' (R = Me)
11a'' (R = t-Bu)
Entry
1
Catalyst
10
Solvent
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
MeCN
THF
Temp (°C)
r.t.
Yield (%)b
ee (%)c
20
1
2
3
4
5
5
5
5
5
5
5
5
5
10a
10a
10a
10a
10a
10a¢
10a¢¢
10a
10a
10a
10a
10a
10a
94
72
31
60
89
86
62
78
65
91
85
90
52
2
r.t.
20
3
r.t.
50
4
r.t.
42
5
r.t.
60
6
r.t.
52
7
r.t.
25
8
r.t.
56
9
r.t.
54
10
11d
12e
13e
CHCl3
r.t.
65
CHCl3
0
80
CHCl3
CHCl3
–10
–20
91
91
a Unless otherwise specified, all reactions were carried out with acetone (0.25 mL), glyoxylate (0.5 mmol), and the catalyst (0.05 mmol,
10 mol%) in the specified solvent (0.25 mL) for 10 h.
b Yield of isolated products after flash chromatography.
c Determined by chiral GC analysis with a Chiraldex GTA column. The absolute configuration was determined through the comparison of the
observed optical rotation with the reported data (ref. 14).
d Reaction time: 24 h.
e Reaction time: 48 h.
99%, (iii) H2/Pd-C (10%), MeOH, 98%.
solubility in acetone. Indeed, protecting the terminal
carboxylic group of catalyst 3 as its methyl ester, which
gives catalyst 4,12b results in much a better yield (60%) of
By using acetone (9a) and ethyl glyoxylate (10a) as the
11a (entry 4). Unfortunately, the ee value of the product
dropped to 42% (entry 4). These results indicate that the
terminal carboxylic acid proton is beneficial for the enan-
tioselectivity, whereas the solubility of the catalyst in the
reaction system is important for its reactivity. Therefore,
the new catalyst 5, possessing an acetyloxy group at the
C-4 position of the proline backbone, was designed and
synthesized (Scheme 1). This design is to keep the enan-
tioselectivity of 3 but to increase the reactivity through
enhanced solubility. To our pleasure, under similar condi-
tions, catalyst 5 gave the aldol product 11a in 89% yield
with an ee value of 60% (entry 5).
model compounds, the reactivity and asymmetric induc-
tion of the above catalysts (1–5, Figure 1) were screened
and the results are summarized in Table 1.
When 10 mol% of L-prolinamide (1) was used as the cat-
alyst, the reaction in excessive acetone as the solvent gave
the desired secondary a-hydroxy carboxylate product 11a
in 94% yield after 10 hours at room temperature, albeit
with a very low ee value of only 20% (entry 1). Under
similar conditions, L-proline also led to 20% ee of the
product (entry 2). These results are in striking contrast to
those of a-ketophosphonates, where these catalysts lead to
excellent enantioselectivities.11b,c
The size of the ester group of the gyloxylate substrate was
also probed. Both the smaller methyl ester (10a¢, entry 6)
and the larger tert-butyl ester (10a¢¢, entry 7) were found
to give inferior enantioselectivities under similar condi-
tions than the ethyl ester (entry 5). Thus, the size of the
ester group plays an important role on the enantioselec-
Dipeptide catalysts such as 37f and 412b have been success-
fully applied in asymmetric aldol reactions and, therefore,
they were also screened in the current study. The dipep-
tide catalyst 37f produced the desired product 11a in a
much improved enantioselectivity (50%); nevertheless,
the yield was much lower (31%, entry 3). This low
reactivity of catalyst 3 was presumably caused by its poor
Synlett 2007, No. 10, 1605–1609 © Thieme Stuttgart · New York

LETTER
Enantioselective Synthesis of Secondary a-Hydroxycarboxylates
1607
tivity, and ethyl gyloxylate (10a) was identified as the best 10 mol% catalyst loading, and CHCl3 as the solvent).15
substrate for catalyst 5. The results are summarized in Table 2.
The reaction conditions were further optimized in order to Besides acetone (entry 1), other aliphatic ketones, such as
obtain the highest enantioselectivity in this reaction. As 2-butanone (9b, entry 2), 2-pentanone (9c, entry 3) and 4-
shown in Table 1, at room temperature, the best enantio- methyl-2-pentanone (9d, entry 4), also participate in this
selectivity (65% ee) was obtained when CHCl3 was used reaction. The aldol reaction of 2-butanone leads to the
as the solvent (entry 10), whereas MeCN (entry 8) and formation of two regioisomers in a 1.5:1 ratio with a com-
THF (entry 9) proved to be worse solvents. Further opti- bined yield of 70%. The major regioisomer 11b is a ther-
mization of the reaction temperature led to an increase of modynamic product, which was obtained in 90% de for
the enantioselectivity. When the temperature was lowered the anti product; and the ee value for this diastereoisomer
to 0 °C, an ee value of 80% was obtained (entry 11). is 98% (entry 2). The minor regioisomer 11b¢ is a kinetic
Similar reaction at –10 °C resulted in the highest enantio- product, which was obtained in 84% ee. The reaction of 2-
selectivity of 91% (entry 12). Nonetheless, further drop- pentanone (9c, entry 3) and 4-methyl-2-pentanone (9d,
ping the reaction temperature to –20 °C did not improve entry 4) with ethyl glyoxylate, however, produces only the
the enantioselectivity, but instead had an adverse effect on kinetic regioisomers 11c and 11d in 62% and 35% yields,
the reactivity of the catalyst (entry 13).
respectively. The ee values of these two products were
74% and 86%, respectively. In contrast, the aldol reaction
of a-methoxyacetone (9e) yielded only the thermodynam-
ic product 11e in a 70:30 diastereomeric ratio with 89%
and 57% ee for the major and minor diastereomers, re-
spectively (entry 5).
The absolute configuration of the newly formed chiral
center in 11a was determined to be R by comparing the
observed optical rotation with the reported data.14
To study the scope of this reaction, a series of ketone sub-
strates was subjected to the optimized conditions (–10 °C,
Cyclic ketones (9f–i) are also good substrates for this re-
action. Cyclopentanone (9f) led to the desired aldol prod-
Table 2 Enantioselective Cross-Aldol Reaction of Ethyl Glyoxylate (7a) and Various Ketonesa
O
OH
O
O
5
*
CO2Et
H
CO2Et
10a
R1
R2
R1
R2
11
9
Entry
R1
R2
H
Product
Yield (%)b
dr
ee (%)c
91
1
2
H
11a
11b
11b¢
11c
11d
11e
11f
90
42d
28d
62
35
56
72
70
74
75
H
Me
H
95:5e
98
Me
84
3f,g
4f,g
5f,g
6
Et
H
74
i-Pr
H
86
OMe
H
70:30e
60:40h
90:10i
80:20i
90:10i
89 (57)
95 (85)
88
–(CH2)2–
–(CH2)3–
–CH2OCH2–
–CH2SCH2–
7
11g
11h
11i
8f
80 (26)
81j
9f
a Unless otherwise specified, all reactions were carried out with the ketone (0.25 mL), ethyl glyoxylate (0.5 mmol), and the catalyst (0.05 mmol,
10 mol%) in CHCl3 (0.25 mL) at –10 °C for 48 h.
b Yields of isolated products after flash chromatography.
c The ee was determined by chiral GC analysis with a Chiraldex GTA column. The stereochemistry of the a-carbon was assigned on the basis
of the reaction mechanism.
d Yields of the individual regioisomer as determined by GC analysis.
e The anti/syn ratio was determined by GC analysis of the crude mixture.
f Reaction time: 72 h.
g 20 mol% of catalyst was used.
h The syn/anti ratio was determined by NMR.
i The anti/syn ratio was determined by NMR.
j The ee was determined by chiral HPLC analysis with a Chiralpak AD-H column.
Synlett 2007, No. 10, 1605–1609 © Thieme Stuttgart · New York

1608
R. Dodda, C.-G. Zhao
LETTER
(8) For selected recent examples, see: (a) Tang, Z.; Jiang, F.;
Yu, L.-T.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu,
Y.-D. J. Am. Chem. Soc. 2003, 125, 5262. (b) Tang, Z.;
Yang, Z.-H.; Chen, X.-H.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-
Z.; Gong, L.-Z. J. Am. Chem. Soc. 2005, 127, 9285.
(c) Samanta, S.; Liu, J.; Dodda, R.; Zhao, C.-G. Org. Lett.
2005, 7, 5321. (d) Luppi, G.; Cozzi, P. G.; Monari, M.;
Kaptein, B.; Broxterman, Q. B.; Tomanisi, C. J. Org, Chem.
2005, 70, 7418. (e) Wang, W.; Li, H.; Wang, J. Tetrahedron
Lett. 2005, 46, 5077. (f) Zheng, J.-F.; Li, Y.-X.; Zhang, S.-
Q.; Yang, S.-T.; Wang, X.-M.; Wang, Y.-Z.; Bai, J.; Liu, F.-
A. Tetrahedron Lett. 2006, 47, 7793. (g) Chen, J.-R.; Lu,
H.-H.; Li, X.-Y.; Cheng, L.; Wan, J.; Xiao, W.-J. Org. Lett.
2005, 7, 4543. (h) Cobb, A. J. A.; Shaw, D. M.;
uct 11f in 72% yield with a diastereomeric ratio of 60:40
(entry 6). The major diastereoisomer, which was deter-
mined to be syn,16 was obtained in 95% ee. The minor anti
diastereoisomer was obtained in 85% ee. Under these con-
ditions, cyclohexanone resulted in a 70% yield of the aldol
product 11g17 in an excellent diastereoselectivity (90:10,
entry 7). The major diastereoisomer, which was deter-
mined to be anti,17 was obtained in 88% ee. Similar results
were also obtained for 4-oxacyclohexanone (9h, entry 8)
and 4-thiacyclohexanone (9i, entry 9), except the ee
values are slightly inferior for the products of these two
substrates (80% and 81% ee, respectively).
Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biomol.
Chem. 2005, 3, 84.
(9) Tang, Z.; Cun, L.-F.; Cui, X. M. i. A.-Q.; Jiang, Y.-Z.; Gong,
L.-Z. Org. Lett. 2006, 8, 1263.
(10) For some isolated examples, see: (a) Tokuda, O.; Kano, T.;
Gao, W.-G.; Ikemoto, T.; Maruoka, K. Org. Lett. 2005, 7,
5103. (b) Suri, J. T.; Mitsumori, S.; Albertshofer, K.;
Tanaka, F.; Barbas, C. F. III J. Org. Chem. 2006, 71, 3822.
(c) Cardova, A.; Zou, W.; Dziedzic, P.; Ibrahem, I.; Reyes,
E.; Xu, Y. Chem. Eur. J. 2006, 12, 5383.
In conclusion, the direct aldol reaction of ethyl glyoxylate
and various ketones has been realized by using the novel
L-proline-derived dipeptide 5 as the organocatalyst. This
catalyst displays good to high enantioselectivities (up to
98% ee) and diastereoselectivities (up to 90% de), espe-
cially when six-membered cyclic ketones are used as the
substrates.
Acknowledgment
(11) (a) Samanta, S.; Zhao, C.-G. Tetrahedron Lett. 2006, 47,
3383. (b) Samanta, S.; Zhao, C.-G. J. Am. Chem. Soc. 2006,
128, 7224. (c) Dodda, R.; Zhao, C.-G. Org. Lett. 2006, 8,
4991. (d) Shen, Z.; Li, B.; Wang, L.; Zhang, Y. Tetrahedron
Lett. 2005, 46, 8785. (e) Guizzetti, S.; Benaglia, M.;
Pignataro, L.; Puglisi, A. Tetrahedron: Asymmetry 2006, 17,
2754. (f) Wu, Y.; Zhang, Y.; Yu, M.; Zhao, G.; Wang, S.
Org. Lett. 2006, 8, 4417. (g) Raj, M.; Vishnumaya; Ginotra,
S. K.; Singh, V. K. Org. Lett. 2006, 8, 4097.
(12) (a) Yoshinori, I.; Shuji, T.; Takeshi, K. J. Antibiotics 1986,
39, 1378. (b) Tang, Z.; Yang, Z.-H.; Cun, L.-F.; Gong, L.-Z.;
Mi, A.-Q.; Jiang, Y.-Z. Org. Lett. 2004, 6, 2285.
(13) Fache, F.; Piva, O. Tetrahedron: Asymmetry 2003, 14, 139.
(14) Gondi, V. B.; Gravel, M.; Rawal, V. H. Org. Lett. 2005, 7,
5657.
The authors thank the Welch Foundation (Grant No. AX-1593) and
the NIH-MBRS program (Grant No. S06 GM08194) for the finan-
cial support of this research.
References and Notes
(1) For a review, see: a-Hydroxy Acids in Enantioselective
Synthesis; Copolla, G. M.; Schuster, H. F., Eds.; Wiley-
VCH: Weinheim, 1997.
(2) (a) Leblond, C.; Wang, J.; Liu, J.; Andrews, A. T.; Sun, Y.-
K. J. Am. Chem. Soc. 1999, 121, 4920. (b) Carpentier, J.-F.;
Mortreux, A. Tetrahedron: Asymmetry 1997, 8, 1083.
(c) Brown, H. C.; Cho, B. T.; Park, W. S. J. Org. Chem.
1986, 51, 3396. (d) Wang, C.-J.; Sun, X.; Zhang, X. Synlett
2006, 1169.
(15) General Experimental Procedure
To a stirred solution of ethyl glyoxylate (51.0 mg, 0.5 mmol)
and the ketone (0.25 mL) in CHCl3 (0.25 mL) was added
catalyst 5 (13.6 mg, 0.05 mmol) at –10 °C. The reaction
mixture was stirred at this temperature for 24–72 h. The
solvent was then evaporated under vacuum and the residue
was purified by flash chromatography (EtOAc–hexane, 1:2)
over silica gel to furnish the desired secondary a-hydroxy-
carboxylate as a pure compound. 1H NMR and 13C NMR
data of new compounds are collected below.
(3) Xiang, Y. B.; Snow, K.; Belley, M. J. Org. Chem. 1993, 58,
993.
(4) (a) Zhu, D.; Stearns, J. E.; Ramirez, M.; Hua, L. Tetrahedron
2006, 62, 4535. (b) Ishihara, K.; Nakajima, N.; Yamaguchi,
H.; Hamada, H.; Uchimura, Y.-S. J. Mol. Catal. B: Enzym.
2001, 15, 101. (c) Nakamura, K.; Inoue, K.; Ushio, K.; Oka,
S.; Ohno, A. J. Org. Chem. 1988, 53, 2589.
(5) (a) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33,
325. (b) Lalic, G.; Aloise, A. D.; Shair, M. D. J. Am. Chem.
Soc. 2003, 125, 2852. (c) Kudyba, I.; Raczko, J.; Jurczak, J.
J. Org. Chem. 2004, 69, 2844.
(6) (a) Kalaritis, P.; Regenye, R. W.; Partridge, J. J.; Ciffen, D.
L. J. Org, Chem. 1990, 55, 812. (b) Huang, S.-H.; Tsai, S.-
W. J. Mol. Catal. B: Enzym. 2004, 28, 65. (c) Liljeblad, A.;
Kanerva, L. T. Tetrahedron: Asymmetry 1999, 10, 4405.
(7) (a) List, B.; Lerner, R. A.; Barbas, C. F. III J. Am. Chem. Soc.
2000, 122, 2395. (b) Notz, W.; List, B. J. Am. Chem. Soc.
2000, 122, 7386. (c) List, B.; Pojarliev, P.; Castello, C. Org.
Lett. 2001, 3, 5773. (d) Sakthivel, K.; Notz, W.; Bui, T.;
Barbas, C. F. III J. Am. Chem. Soc. 2001, 123, 5260.
(e) Pidathala, C.; Hoang, L.; Vignola, N.; List, B. Angew.
Chem. Int. Ed. 2003, 42, 2785. (f) List, B. Synlett 2001,
1675. (g) Martin, H. J.; List, B. Synlett 2003, 1901. For
reviews, see: (h) List, B. Tetrahedron 2002, 58, 5573.
(i) List, B. Acc. Chem. Res. 2004, 37, 548. (j) Notz, W.;
Tanaka, F.; Barbas, C. F. III Acc. Chem. Res. 2004, 37, 580.
Compound 5: 1H NMR (500 MHz, CDCl3): d = 0.83 (t,
J = 7.5 Hz, 6 H), 1.90–1.92 (m, 1 H), 1.99 (s, 3 H), 2.06–2.11
(m, 2 H), 2.96 (d, J = 3.0 Hz, 2 H), 3.79 (t, J = 8.0 Hz, 1 H),
4.12 (q, J = 4.5 Hz, 1 H), 5.08 (d, J = 2.5 Hz, 1 H), 8.10 (d,
J = 9.5 Hz, 1 H, CONH) ppm. 13C NMR (125 MHz, CDCl3):
d = 18.3, 19.8, 21.7, 31.1, 37.6, 53.0, 57.2, 59.9, 76.6, 170.8,
173.5, 173.7 ppm.
Compound 8: 1H NMR (500 MHz, CDCl3): d = 0.72–0.98
(m, 6 H), 2.00–2.40 (m, 3 H), 3.42–3.79 (m, 3 H), 4.38–4.61
(m, 3 H), 5.00–5.33 (m, 4 H), 7.20–7.52 (m, 11 H) ppm. 13
C
NMR (125 MHz, CDCl3): d = 17.8, 19.2, 31.4, 37.3 (40.0),
54.8 (56.0), 57.7 (57.3), 59.3 (59.7), 67.2, 67.7, 70.1 (69.5),
128.1 (2 C), 128.3 (2 C), 128.6 (2 C), 128.7 (2 C), 128.8 (2
C), 135.7, 136.6, 156.4 (155.6), 171.9, 172.7 (171.6) ppm.
Compound 11c: 1H NMR (500 MHz, CDCl3): d = 0.91 (t,
J = 8.3 Hz, 3 H), 1.28 (t, J = 7.0 Hz, 3 H), 1.20 (q, J = 7.3
Hz, 2 H), 2.43 (t, J = 7.5 Hz, 2 H), 2.87 (dd, J = 17.5, 6.5 Hz,
1 H), 2.94 (dd, J = 17.5, 4.0 Hz, 1 H), 4.21–4.30 (m, 2 H),
Synlett 2007, No. 10, 1605–1609 © Thieme Stuttgart · New York

LETTER
Enantioselective Synthesis of Secondary a-Hydroxycarboxylates
1609
4.68 (dd, J = 6.5, 4.0 Hz, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): d = 13.8, 14.3, 17.2, 45.5, 46.1, 62.1, 67.3, 174.0,
208.8 ppm.
Compound 11h (diastereomeric mixture), major isomer: 1H
NMR (500 MHz, CDCl3): d = 1.26 (t, J = 7.0 Hz, 3H ), 2.37
(dt, J = 15.0, 2.0 Hz, 1 H), 2.56–2.63 (m, 1 H), 3.10–3.16 (m,
2 H), 3.70 (td, J = 11.5, 3.0 Hz, 1 H), 3.83 (t, J = 11.0 Hz, 1
H), 4.02 (m, 1 H), 4.18–4.30 (m, 4 H) ppm. 13C NMR (125
MHz, CDCl3): d = 14.3, 42.5, 54.0, 62.3, 68.0, 68.1, 70.0,
173.1, 205.9 ppm.
Compound 11d: 1H NMR (500 MHz, CDCl3): d = 0.88 (d,
J = 7.0 Hz, 6 H), 1.24 (t, J = 7.3 Hz, 3 H), 2.09–2.13 (m, 1
H), 2.28 (d, J = 7.0 Hz, 2 H), 2.83 (dd, J = 17.5, 6.0 Hz, 1 H),
2.86 (dd, J = 17.5, 4.0 Hz, 1 H), 3.19 (br s, 1 H), 4.18–4.22
(m, 2 H), 4.42 (m, 1 H) ppm. 13C NMR (125 MHz, CDCl3):
d = 14.3, 22.7 (2 C), 24.8, 46.6, 52.5, 62.1, 67.2, 174.0,
208.5 ppm.
Compound 11h (diastereomeric mixture), minor isomer: 1H
NMR (500 MHz, CDCl3): d = 1.27 (t, J = 7.0 Hz, 3 H), 2.47
(dt, J = 15.0, 3.5 Hz, 1 H), 2.56–2.63 (m, 1 H), 2.85–2.98 (m,
2 H), 3.77 (td, J = 10.5, 4.0 Hz, 1 H), 3.89 (t, J = 9.5 Hz, 1
H), 4.03–4.18 (m, 1 H), 4.12–4.30 (m, 3 H), 4.65 (d, J = 3.5
Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): d = 14.4, 42.5,
54.7, 62.4, 67.5, 68.2, 68.3, 173.4, 205.5 ppm.
Compound 11e (diastereomeric mixture), major isomer: 1H
NMR (500 MHz, CDCl3): d = 1.30 (t, J = 7.5 Hz, 3 H), 2.25,
(s, 3 H), 3.56 (s, 3 H), 3.94 (d, J = 2.5 Hz, 1 H), 4.20–4.4.28
(m, 2 H), 4.58 (d, J = 2.5 Hz, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): d = 14.3, 27.4, 60.2, 62.6, 72.3, 89.0, 171.6, 208.5
ppm.
Compound 11i: 1H NMR (500 MHz, CDCl3): d = 1.28 (t,
J = 7.0 Hz, 3 H), 2.64–2.78 (m, 2 H), 2.89–3.10 (m, 3 H),
3.13 (br s, 1 H), 3.18–3.30 (m, 2 H), 4.13 (m, 1 H), 4.25 (q,
J = 7.2 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3): d =
14.3, 29.9, 32.6, 44.4, 56.0, 62.2, 71.0, 172.9, 208.0 ppm.
(16) Tsuboi, S.; Nishiyama, E.; Furutani, H.; Utaka, M.; Takeda,
A. J. Org. Chem. 1987, 52, 1359.
Compound 11e (diastereomeric mixture), minor isomer: 1H
NMR (500 MHz, CDCl3): d = 1.33 (t, J = 7.5 Hz, 3 H), 2.29
(s, 3 H), 3.44 (s, 3 H), 3.95 (d, J = 2.5 Hz, 1 H), 4.28–4.30
(m, 2 H), 4.50 (d, J = 2.0 Hz, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): d = 14.5, 27.5, 59.9, 62.4, 72.1, 87.7, 171.9, 209.9
ppm.
(17) Matsubara, R.; Nakamura, Y.; Kobayashi, S. Angew. Chem.
Int. Ed. 2004, 43, 3258.
Synlett 2007, No. 10, 1605–1609 © Thieme Stuttgart · New York

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