Aldolase-catalyzed asymmetric synthesis of novel pyranose synthons as a new entry to heterocycles and epothilones

Article abstract of DOI:10.1002/1521-3773(20020415)41:8<1404::AID-ANIE1404>3.0.CO;2-G

Enzymatic reactions catalyzed by DERA provide the basis for a new strategy for the synthesis of novel pyranose synthons. The utility of this very convergent and effective method is demonstrated by the concise total synthesis of epothilones (see scheme; DERA = 2-deoxyribose-5-phosphate aldolase).

Full text of DOI:10.1002/1521-3773(20020415)41:8<1404::AID-ANIE1404>3.0.CO;2-G

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40 mA) with graphite monochromated MoKa radiation (l ˆ
0.71069 ä) at 150 K. The structure was solved by direct methods, by
using SIR-92, and refined by full-matrix least-squares analysis on F. A
total of 6392 reflections were measured, and of these, 4509 reflections
[Fo > 3.00s(Fo)] were used in refinement: R ˆ 0.041, Rw ˆ 0.044.
CCDC-175782 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge via www.ccdc.ca-
m.ac.uk/conts/retrieving.html (or from the Cambridge Crystallo-
graphic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK;
fax: (‡44)1223-336-033; or deposit@ccdc.cam.ac.uk).
tivity was completely opposite to that for the alcohol addition
to common silaethenes, which indicates the significant con-
tribution of the resonance form B in 1b (Scheme 1); the OH
hydrogen and methoxy groups of methanol were bonded to
the unsaturated silicon atom and a ring carbon atom in 1b,
respectively.[16]
Received: December 14, 2001 [Z18381]
[13] The bend angles q and g are defined as the angles between the three-
À
membered-ring plane and the Si(unsaturated) C bond, and between
À
the R2Si plane and the Si(unsaturated) C bond, respectively
[1] For recent reviews on silaethenes, see: a) M. A. Chaubon, H.
Ranaivonjatovo, J. Escudie, J. Satge, Main Group Met. Chem. 1996,
19, 145 160; b) A. G. Brook, M. A. Brook, Adv. Organomet. Chem.
1996, 39, 71 158; c) T. M¸ller, W. Ziche, N. Auner in The Chemistryof
Organosilicon Compounds, Vol. 2, Part 2 (Eds.: Z. Rappoport, Y.
Apeloig), Wiley, New York, 1998, chap. 16, pp. 857 1062.
[2] K. Sakamoto, J. Ogasawara, H. Sakurai, M. Kira, J. Am. Chem. Soc.
1997, 119, 3405 3406.
[3] For recent theoretical studies of 4-silatriafulvenes, see: a) G. W.
Schriver, M. J. Fink, M. S. Gordon, Organometallics 1987, 6, 1977
1984; b) S. M. Bachrach, M. Liu, J. Phys. Org. Chem. 1991, 4, 242
250; c) P. Burk, J.-L. M. Abboud, I. A. Koppel, J. Phys. Chem. 1996,
(Scheme 2). Theoretical bend angles q and g for 1c in the bent
structure are 171.8 and 141.58, respectively.[3g]
[14] The reaction of 1b with tert-butyl alcohol in hexane under reflux
afforded the alcohol adducts of the corresponding silacyclobutadiene
as expected.[2] Details will be reported elsewhere.
[15] 3: a colorless oil; 1H NMR (300 MHz, C6D6): d ˆ 0.21 (s, 3H), 0.25
(s  2, 6H), 0.27(s, 3H), 1.00 (s  2, 18H), 1.18 (s, 9H), 1.22 (s, 9H),
3.02 (s, 3H), 4.24 (s, 1H); 13C NMR (75 MHz, C6D6): d ˆ À2.92, À2.87,
À2.60, À2.41, 18.51, 18.59, 27.65, 29.41, 30.51, 32.73, 38.09, 53.95, 76.42,
115.25, 156.53; 29Si NMR (59 MHz, C6D6): d ˆ À90.24 (d, J(Si,H) ˆ
1
‡
155 Hz), À1.92, À1.43; MS (70 eV) m/z (%) 425 (M À 15, 6), 259 (6),
¬
147(100), 115 (6).
100, 6992 6997; d) T. Veszpremi, M. Takahashi, J. Ogasawara, K.
[16] Similar inverted regioselectivity has been observed for a silacalicene
Sakamoto, M. Kira, J. Am. Chem. Soc. 1998, 120, 2408 2414; e) T.
by West et al.[5]
¬
¬
Veszpremi, M. Takahashi, B. Hajgato, J. Ogasawara, K. Sakamoto, M.
Kira, J. Phys. Soc. A 1998, 102, 10530 10535; f) S. Saebo, S. Stroble,
W. Collier, R. Ethridge, Z. Wilson, M. Tahai, C. U. Pittman, Jr., J. Org.
Chem. 1999, 64, 1311 1318; g) M. Takahashi, K. Sakamoto, M. Kira,
Int. J. Quantum. Chem. 2001, 84, 198 207.
[4] H. Schumann, M. Glanz, F. Girgsdies, F. E. Hahn, M. Tamm, A.
Grzegorzewski, Angew. Chem. 1997, 109, 2328 2330; Angew. Chem.
Int. Ed. Engl. 1997, 36, 2232 2234.
[5] Recently, West et al. have presented synthesis and properties of
hexaphenylsilacalicene and hexaphenylgermacalicene: R. West, H.
Sohn, Y. Apeloig, T. Mueller in 11th International Symposium on
Organosilicon Chemistry (Montpelier, France), 1996, LA2.
Aldolase-Catalyzed Asymmetric Synthesis of
Novel Pyranose Synthons as a New Entry to
Heterocycles and Epothilones**
[6] a) D. Bravo-Zhivotovskii, V. Braude, A. Stanger, M. Kapon, Y.
Apeloig, Organometallics 1992, 11, 2326 2328; b) Y. Apeloig, M.
Bendikov, M. Yuzefovich, M. Nakash, D. Bravo-Zhivotovskii, D.
Blaser, R. Boese, J. Am. Chem. Soc. 1996, 118, 12228 12229.
[7] a) C. Krempner, H. Reinke, H. Oehme, Chem. Ber. 1995, 128, 1083
1088; b) F. Luderer, H. Reinke, H. Oehme, J. Organomet. Chem. 1996,
510, 181 188; c) C. Wendler, H. Oehme, Z. Anorg. Allg. Chem. 1996,
622, 801 806; d) F. Luderer, H. Reinke, H. Oehme, Chem. Ber. 1996,
129, 15 20; e) D. Hoffmann, H. Reinke, H. Oehme, J. Organomet.
Chem. 1996, 526, 185 189.
Junjie Liu and Chi-Huey Wong*
The enzyme 2-deoxyribose-5-phosphate aldolase (DERA,
EC 4.1.2.4), a Schiff base forming type I class aldolase,
catalyzes the reversible aldol reaction of acetaldehyde and d-
glyceraldehyde 3-phosphate (G3P) to form d-2-deoxyribose-
5-phosphate (DRP).[1] The enzyme has been overexpressed in
Escherichia coli, and its structure and catalytic mechanism
have been determined at the atomic level.[2]
DERA accepts a broad range of acceptor and donor
aldehydes in addition to the natural substrates.[1] An interest-
ing transformation is the sequential asymmetric aldol addition
reaction of three achiral aldehydes to form pyranoses with
two new stereogenic centers (Scheme 1A).[3] In this sequen-
tial reaction, the first aldol product acts as a substrate for the
second aldol reaction to give an enantiomerically pure 3,5-
[8] 1b: Yellow crystals; m.p. 958C (decomp.); 1H NMR (300 MHz,
[D6]benzene, TMS): d ˆ 0.47(s, 12H), 1.16 (s, 18H), 1.17(s, 18H);
13C NMR (75 MHz, [D6]benzene, TMS): d ˆ 0.2, 19.6, 28.5, 28.6, 32.9,
1
157.0 (C C), 159.9 (Si C, JSi,C ˆ 66 Hz); 29Si NMR (59 MHz,
ˆ
ˆ
1
ˆ
[D6]benzene, TMS): d ˆ À71.9 (Si C, JSi,C ˆ 66 Hz), 1.7(Si tBuMe2);
HRMS calcd for C23H48Si3 408.3064 found 408.3060.
ˆ
[9] Typical dSi values for (Me3SiO)(Ad)C Si(SiMe3)2 (Ad ˆ adamantyl)
and (Me3Si)(tBuMe2Si)C SiMe2 are ‡42 and ‡144, respectively.[10]
ˆ
Recently, negative dSi values for the unsaturated silicon nuclei have
been found in 1-aza-3-silaallene (dSi ˆ À57)[11] and hexaphenylsilaca-
licene (dSi ˆ À28),[5] with rather less polar Si C double bonds.
À
[10] a) A. G. Brook, S. C. Nyburg, F. Abdesaken, B. Gutekunst, G.
Gutekunst, R. Krishna, M. R. Kallury, Y. C. Poon, Y.-M. Chang, W.-
N. Winnie, J. Am. Chem. Soc. 1982, 104, 5667 5672; b) N. Wiberg, G.
Wagner, G. Mueller, Angew. Chem. 1985, 97, 220 222; Angew. Chem.
Int. Ed. Engl. 1985, 24, 229 231.
[*] Prof. Dr. C.-H. Wong, J. Liu
Department of Chemistry and the Skaggs Institute for Chemical
Biology
The Scripps Research Institute, La Jolla, CA 92037(USA)
Fax :(‡1)858-784-2409
[11] N. Takeda, H. Suzuki, N. Tokitoh, R. Okazaki, S. Nagase, J. Am.
Chem. Soc. 1997, 119, 1456 1457.
E-mail: wong@scripps.edu
[**] This work was supported by the NIH GH44154. We thank Dr. G.-J.
Shen for the preparation of 2-deoxyribose-5-phosphate aldolase
(DERA) and Dr. D.-H. Huang and Dr. L. B. Pasternack for NMR
assistance.
[12] Recrystallization of 1b from heptane gave single crystals suitable for
X-ray structural analysis. X-ray analysis of 1b: MF ˆ C23H48Si3, MW
ˆ
408.89, monoclinic, space group P21/c, a ˆ 11.0141(8), b ˆ 17.9026(9),
c ˆ 14.210(3) ä, b ˆ 91.173(2)8, Vˆ 2801.4(7) ä3, Z ˆ 4, 1calcd
ˆ
0.969 gcmÀ3, m(MoKa) ˆ 1.75 cmÀ1. The reflection intensities were
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
collected on a Rigaku/MSC Mercury CCD diffractometer (50 kV,
1404
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group is at the C2 position (Table 1, entries 5
7): 5a afforded lactone 5b in 48% yield after
two steps, while its enantiomer 6a only gave 6b
in trace amounts, and racemic aldehyde 7a only
produced 7b. Molecular modeling based on the
structure of DERA[2] reveals a hydrophilic
binding pocket composed of Thr170 and
Lys172 for the OH group at C2 and a hydro-
phobic pocket for the H atom at C2. A switch
of the binding was observed for 5a and 7a in
which the methyl and the methoxy groups are
in the hydrophobic pocket, which results in the change of
enantioselectivity.
O
OH
R
O
A)
B)
O
O
OH OH
O
DERA
R
H
R
OH
R = H, N3, Cl, MeO
O
O
O
O
OH
OH
O
O
b)
a)
H
HO
HO
DERA
R
R
R
R
OH
OH
Scheme 1. Preparation of unnatural pyranoses with DERA. a) pH 7.5, DERA, acetaldehyde;
b) Br2, BaCO3. For details of routes A and B see text.
dihydroxyaldehyde which then cyclizes to form the stable
pyranose, thus driving the reaction toward condensation.
Since these 1,3-polyol systems are useful synthons,[4] we have
further examined the scope of this enzymatic methodology.
Our strategy is to exploit b-hydroxyaldehydes as acceptors
(Scheme 1B) to generate the products which would cyclize to
form stable hemiacetals, thus driving the reaction toward
condensation. The hemiacetal could be further oxidized to
give a lactone. We have found that the oxidation sometimes
makes the purification much easier, and more importantly, the
lactone can be further transformed to other useful synthons.
Several different substrates have been tested and the results
are summarized in Table 1.
The 1,3-polyol systems prepared from the enzymatic
8]
reaction could serve as useful synthons.[5 An example is
the stereoselective C2 alkylation of b-hydroxylactone with an
alkyl bromide under chelation control directed by the b-
hydroxy group (Scheme 2).[9] This reaction can provide more
diversified pyranoses after reduction of the lactones[10] and
generate additional useful intermediates for organic synthesis.
In our alkylation experiment, the other diastereomers were
not detected. The relative configuration of 9a was unequiv-
ocally confirmed by NMR experiments.
The configuration of C2 in the acceptor aldehydes is very
critical for the enzymatic reaction. We found that d isomers
were overwhelmingly preferred over l isomers when polar
groups (e.g. OH, N3) were at this position; when racemic
acceptor aldehydes were used, only the d isomer products
were formed (Table 1, entries 2 4). On the contrary, an
opposite enantioselectivity was observed when a hydrophobic
O
O
O
O
O
OH
a)
b)
n
OH
OH
OH
9a n=1, 85%
9b n= 3, 32%
8
5b
Scheme 2. Stereoselective alkylation. a) Br2, BaCO3, 12 h, 62%; b) LDA,
HMPA, À788C, alkene bromide, 36 h. LDA ˆ lithium diisopropylamide,
HMPA ˆ hexamethylphosphoramide.
Table 1. Aldol condensation catalyzed by DERA.
The availability of both intermediates 9a and 9b permitted
n]
us to choose either the Suzuki coupling[11a,b,k or olefin
Entry Acceptor
Donor t [days] Product
Yield [%]
65
metathesis strategy[11c h,p,q] to prepare epothilones as potential
anticancer agents.[12] Since allyl bromide is more active and
gives 9a in a higher yield, the Suzuki coupling strategy was
chosen for the construction of the C12 C13 Z double bond
(Scheme 3). In addition to 9a, compound 11 prepared by
DERA was also used as a key synthon.[13]
1
3
2
3
4
5
6
7
3
3
6
3
6
6
60[a]
In our synthesis of fragment A (Scheme 4), the lactone ring
of 9a was first opened to afford diol 12, which was then
protected as the PMP acetal. After reduction by LiAlH4, the
hydroxy was removed by mesylation followed by reduction,
both in excellent yield.[14] Regioselective cleavage of the PMP
protecting group in 13 with DIBAL in toluene gave the
primary alcohol as the only product, which was oxidized with
Dess Martin periodinane[15] to give aldehyde 14. Compound
14 was then condensed with tert-butyl isobutyrylacetate[11b, 16]
to give compound 15 in 70% yield (d.r. 8:1). Stereoselective
47[a]
28[a]
48[b]
trace[b]
22[a]
[17]
reduction with Me4NBH(AcO)3 resulted in the formation
of the desired diol (d.r. 10:1). Regioselective silylation of the
b-hydroxy group followed by oxidation gave fragment A.
Because the configuration of C2 in 16 is not essential in our
synthetic route (Scheme 5), racemic lactaldehyde acetal 16
was used in our current synthesis. Interestingly, we found that
only the d isomer was accepted as a substrate for DERA and
no l isomer product was detected in our experiment.
[a] Based on the reactive enantiomers. [b] Total yield for two steps from
protected aldehyde.
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afforded 19.[11b, 18] Following deprotection of the
S
dithiane with Hg(OCl4)2,[19] the aldehyde product
O
OH
OH
DERA
I
‡
was directly coupled with (Ph3P CH2I)IÀ[20] to
N
HO
afford fragment B in 60% yield for the two steps.
The Suzuki coupling of fragments A and B
proceeded smoothly as described by Danishefsky
et al.[11b] to afford 20 (Scheme 6). After the acetyl
and tert-butyl ester protecting groups were
removed, the hydroxy acid 21 was subject to
Yamaguchi macrolactonization conditions[21] to
afford the intermediate 22. The PMP and TBS
protecting groups were removed with DDQ[22]
and HF ¥ pyr, respectively, to furnish epothil-
one C (Epo C). Epoxidation with a freshly
prepared solution of 1,3-dimethydioxirane
(DMDO)[23] afforded synthetic epothilone A
(Epo A) with physical properties ([a]D, 1H,
13C NMR, MS, IR) identical to the reported
data.[11g]
O
OAc
B
11
10
O
S
N
HO
O
O
O
O
OH
Epothilone A
O
HO
HO
O
DERA
PMPO
O
5a
OtBu
8
A
OTBS
O
O
Scheme 3. Retrosynthesis of epothilone A and C. PMP ˆ 4-methoxyphenyl, TBS ˆ tert-
butyldimethylsilyl.
PMP
O
O
OH OH
O
OPMP
f, g)
a)
b-e)
O
O
In summary, we have developed a new strategy
for the synthesis of unnatural pyranose synthons
through enzymatic reactions catalyzed by DE-
RA. This strategy is very convergent and effec-
tive. Coupled with b-hydroxy-directed highly
stereoselective alkylation, diversified 1,3-polyols
can be prepared. Their application to natural
product synthesis has been illustrated by the
concise total synthesis of epothilones A and C.
CO2Me
OH
13
9a
12
14
PMPO
OtBu
PMPO
i-k)
OtBu
O
O
OtBu
h)
OH
O
O
OTBS
O
O
15
A
Received: December 17, 2001 [Z18398]
Scheme 4. Synthesis of fragment A. a) MeONa, À308C, 60%; b) anisaldehyde dimethyl
acetal, CSA, 95%; c) LiAlH4, 08C RT, 90%; d) MsCl, NEt3, 94%; e) LiAlH4, 88%;
f) DIBAL, toluene, 93%; g) Dess-Martin oxidation, 96%; h) NaH, nBuLi, 08C, 70%;
i) Me4NBH(OAc)3, À308C, 83%; j) TBSOTf, 2,6-lutidine, 08C, 10 min, 100%; k) Dess
Martin oxidation, 3 h, 90%. CSA ˆ 10-camphorsulfonic acid, PMP ˆ 4-methoxyphenyl,
Ms ˆ mesyl ˆ methanesulfonyl, DIBAL ˆ diisobutylaluminum hydride, TBS ˆ tert-butyldi-
methylsilyl, Tf ˆ triflate ˆ trifluoromethanesulfonyl.
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OH
OAc
O
S
S
OH
a)
b-d)
OMe
HO
OMe
OH
11
17
16
e)
OAc
[5] I. F. Pelyvas, C. Monneret, P. Herchzegh, Synthetic Aspects of Amino-
deoxySugars and Antibiotics , Springer, New York, 1998.
S
S
g, h)
f)
S
S
B
N
S
S
S
N
S
N
P(O)Ph2
OAc
O
N
PMPO
a)
PMP
O
19
18
b-d)
A
B
OH
OAc
‡
CO2H
OTBS
CO2tBu
OTBS
Scheme 5. Synthesis of fragment B. a) Dowex(H ), 408C, then pH 7.5,
DERA, acetaldehyde, three days, 38% (two steps based on the
O
O
d
21
20
enantiomer); b) AcCl, pyr, 95%; c) BF3 ¥ Et2O, H2O/CH3CN, 08C, 84%;
d) 1,3-propanedithiol, TiCl4, À788C, 97%; e) DMSO, (COCl)2, 95%;
f) nBuLi, THF, À788C, 88%; g) Hg(ClO4)2, CaCO3, THF/H2O, RT, 2 h ;
e)
S
S
HO
N
PMPO
N
ˆ
Epo A
h) Ph3P CHI, NaN(TMS)2, HMPA, THF, À788C. 60% (two steps). Ac ˆ
O
f, g)
h)
O
acetyl, pyr ˆ pyridine, DMSO ˆ dimethyl sulfoxide, THF ˆ tetrahydrofur-
an, TMS ˆ trimethylsilyl.
O
OH O
O
OTBSO
Epo C
22
Scheme 6. Final steps for the synthesis of epothilone A. a) [PdCl2(dppf)2],
Ph3As, Cs2CO3, 9-BBN, 65%; b) MeONa(cat.), MeOH, 85%; c) TMSOTf,
2,6-lutidine; d) NaOH(cat.) MeOH, 78% for two steps; e) Yamaguchi
conditions, 85%; f) DDQ, CH2Cl2, 99%; g) HF ¥ Pyr. THF, 95%;
h) DMDO, 45%. dppf ˆ bis(diphenylphosphanyl)ferrocene, 9-BBN ˆ 9-
borabicyclo[3,3,1]nonane, DDQ ˆ 2,3-dichloro-5,6-dicyano-1,4-benzoqui-
none, DMDO ˆ 3,3-dimethyldioxirane.
The preparation of fragment B is rather straightforward
(Scheme 5). The b-hydroxy group of 11 was selectively
protected and the hemiacetal was treated with 1,3-propane-
dithiol to afford the dithiane 17, which was oxidized to ketone
18 in 95% yield. Wittig reaction of 18 with a phosphine oxide
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COMMUNICATIONS
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Scheme 1. A X: Radical precursor; B, C: radical acceptors.
coupling partners.[3] This limitation could be attributed to the
difficulty in the selective reaction of the transient radicals, for
example, I×, II×, and III×, with certain coupling partners in
radical chain reactions. The problem might be solved if we
could prepare the radical intermediates I×, II×, and III× as their
radical precursors I, II, and III, and subsequently couple them
with radical acceptors in an atom- or group-transfer manner
(Scheme 1).[4] The reaction would then be an iterative atom-
or group-transfer radical reaction.[5] However, there have
been no reports of such transformations, with the exception of
living radical polymerization, in which the same alkenes react
consecutively.[6]
We have reported the group-transfer coupling of tri-
methylsilyl phenyl telluride (1), carbonyl compounds, and
isonitriles, which involves the selective carbon carbon bond
formation of the a-siloxy radical 2 with isonitriles.[7] It should
be noted that the reaction of silyl tellurides with carbonyl
compounds in the absence of isonitrile afforded the a-siloxy
telluride 3. This unique feature of the reaction prompted us to
investigate alkynes as a third coupling partner (Scheme 2).
Here we report a novel group-transfer coupling of 1, carbonyl
compounds, and alkynes to give the silylated allylic alcohol 5.
As the product also possesses a reactive carbon tellurium
bond, radical-mediated transformation via the vinyl radical 4
[20] G. Stork, K. Zhao, Tetrahedron Lett. 1989, 30, 2173 2174.
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Chem. Soc. Jpn. 1979, 52, 1989.
[22] K. Horita, T. Yoshioka, T. Tanaka, Y. Oikawa, O. Yonemitsu,
Tetrahedron 1986, 42, 3021 3028.
[*] Prof. S. Yamago, Prof. J. Yoshida, M. Miyoshi, Dr. H. Miyazoe
Department of Synthetic Chemistry and Biological Chemistry
Graduate School of Engineering
Kyoto University, Kyoto 606-8501 (Japan)
Fax : (‡81)75-753-5911
[23] R. W. Murray, R. Jeyaraman, J. Org. Chem. 1985, 50, 2847 2853.
E-mail: yamago@sbchem.kyoto-u.ac.jp
yoshida@sbchem.kyoto-u.ac.jp
[**] This work was partly supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science, Sports, and
Culture, Japan. We thank Dr. K. Itami for the X-ray analysis.
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
Angew. Chem. Int. Ed. 2002, 41, No. 8
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
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