Diastereoselective Synthesis of Cephalotaxus Esters via Asymmetric Mukaiyama Aldol Reaction

Article abstract of DOI:10.1021/acs.orglett.7b00743

We report a protocol for efficient stereoselective installation of the chiral oxygen-containing tetrasubstituted tertiary carbon stereocenter of the side chain of cephalotaxus esters by means of highly diastereoselective Mukaiyama aldol reactions between α-keto esters (2) and a (Z)-α-chloro ketene silyl acetal. This protocol permitted synthesis of cephalotaxus esters including six natural products in good to excellent yields (up to 94%) with high diastereoselectivities (dr up to 97:3) and could be performed on a multigram scale.

Full text of DOI:10.1021/acs.orglett.7b00743

Letter
pubs.acs.org/OrgLett
Diastereoselective Synthesis of Cephalotaxus Esters via Asymmetric
Mukaiyama Aldol Reaction
Guo-Zhen Ma,†,§ Peng-Fei Li,†,§ Lu Liu,† Wei-Dong Z. Li,‡ and Li Chen*,†
†State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, P. R.
China
‡Innovative Drug Research Centre, Chongqing University, Chongqing 401331, P. R. China
S
* Supporting Information
ABSTRACT: We report a protocol for efficient stereo-
selective installation of the chiral oxygen-containing tetrasub-
stituted tertiary carbon stereocenter of the side chain of
cephalotaxus esters by means of highly diastereoselective
Mukaiyama aldol reactions between α-keto esters (2) and a
(Z)-α-chloro ketene silyl acetal. This protocol permitted
synthesis of cephalotaxus esters including six natural products
in good to excellent yields (up to 94%) with high
diastereoselectivities (dr up to 97:3) and could be performed on a multigram scale.
ephalotaxus esters 1 (R ≠ H), a group of alkaloids
The chiral side chains, which are nonracemic monoacids, are
generally synthesized based upon Seebach’s procedure for the
alkylation of D-malic acid derivative5a or from the correspond-
ing nonracemic chiral epoxides prepared from commercially
available monomethyl itaconate,5b and the side chains are
subsequently joined with cephalotaxine (1a) to yield the
corresponding cephalotaxus esters (1, R ≠ H). However, owing
to the formidable steric bulk of both the pentacyclic
diterpenoid skeleton and the α-tetrasubstituted monoacids,6
only a cyclic monoacid, such as a tetrahydropyran7 or a
lactone,8 can smoothly couple with 1a to afford the desired
product in good to high yields (Scheme 1). For example, chiral
cyclic monoacids synthesized from readily available chiral
materials such as D-malic acid9 or generated by chiral resolving
reagents such as (−)-quinine10 have been used for cephalotaxus
ester synthesis. In addition, parent alkaloid 1a has been used as
a chiral auxiliary for the enantioselective construction of the
chiral oxygen-containing carbon stereocenter by means of a
Reformatsky reaction or a related 1,2-addition reaction of the
α-keto ester derived from 1a.11 However, in most cases, the
diastereoselectivities of these reactions are rather low. For
example, Mikolajczak reported that the addition of methox-
ycarbonylmethyllithium (LiCH2CO2Me) to an α-keto ester
derived from 1a yielded deoxyharringtonine (1b) in only 6%
yield, along with epi-deoxyharringtonine (epi-1b) in 9%
yield.11b Reformatsky reaction of the α,ε-diketoester of 1a
gave the addition product in excellent yield (90.5%), but
reaction of the addition product with methyllithium afforded
homoharringtonine (1d) in only 10% yield.7 These results
indicate that the enantioselective construction of the chiral
C
isolated as minor components from conifers of the
Cephalotaxus genus,1 have received considerable synthetic
attention owing to their potent antileukemia activity and their
unique pentacyclic ring structure with a side chain bearing an
oxygen-containing chiral carbon center (Figure 1). Recently,
Figure 1. Structures of Cephalotaxus esters.
one member of the group, homoharringtonine (1d), was
approved for the treatment of adults with chronic- or
accelerated-phase chronic myeloid leukemia that is resistant
or tolerant to at least two tyrosine kinase inhibitors,2 and this
drug may be useful as a new frontline treatment for low- and
intermediate-risk patients with acute myeloid leukemia.3 This
biological activity highlights the importance of synthetic studies
of cephalotaxus esters. However, most of the reported studies
have involved the development of efficient methods for
construction of the pentacyclic diterpenoid skeleton, cepha-
lotaxine (1a), and relatively little effort has been devoted to
enantioselective installation of side chains with a chiral oxygen-
containing tetrasubstituted tertiary carbon center.4
Received: March 13, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00743
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Letter
reaction with 3a or 3b for 12 h, we obtained 1b14 in good yields
and low to moderate diastereoselectivities (Table 1, entries 1
Scheme 1. Diastereoselective Synthesis of Cephalotaxus
Esters
Table 1. Optimization of Conditions for Mukaiyama Aldol
a
Reactions of 2a with Ketene Silyl Acetals 3
b
c,d
entry
3
Lewis acid temp (°C) time (h) yield (%)
dr
1
3a
3b
3b
3b
3b
3b
3b
3c
3c
3d
3d
3d
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
TiCl4
−20
−20
−40
−60
−20
−25
−40
0
12
12
12
12
60
60
20
22
22
12
12
24
60
60:40
75:25
77:23
80:20
16:84
20:80
42:58
2
80
3
90
4
95
e
e
5
60 (50)
62 (50)
74
6
SnCl4
7
ZnBr2
f
8
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
35
>99:1
f
9
−25
−40
−60
−78
40
>99:1
g
10
11
12
90
96:4
g
92
97:3
g
oxygen-containing tetrasubstituted tertiary carbon stereocenter
of the side chains of cephalotaxus esters remains a challenge.
To address this challenge, we investigated the use of chiral
auxiliary-induced asymmetric Mukaiyama aldol reaction of α-
ketoesters, a reaction that has been studied by various research
groups.12 For example, using optically active bulky 8-phenyl-
menthol or cyclitol as a chiral auxiliary, Chen and Fang12a and
Akiyama et al.12b synthesized a series of chiral α-hydroxyl esters
with a chiral tetrasubstituted tertiary carbon stereocenter with
good to excellent diastereoselectivities by reactions of the
corresponding α-ketoesters with ketene silyl acetals. These
reactions represent the only two reported examples of
asymmetric Mukaiyama aldol reaction of α-ketoesters with
chiral auxiliaries on the ester groups, but these examples
suggested to us that this method was promising for the
installation of the chiral oxygen-containing tetrasubstituted
tertiary carbon stereocenter of the cephalotaxus esters.
In this study, we found that although cephalotaxine (1a) was
not an efficient chiral auxiliary for reactions of simple ketene
silyl acetals, introduction of a halide atom at the α-position of
the ketene silyl acetal markedly improved the diastereoselec-
tivity of the reaction.13 Specifically, we report herein that
asymmetric Mukaiyama aldol reactions of α-ketoesters 2
derived from 1a with (Z)-α-chloro-substituted ketene silyl
acetal 3d13a followed by dechlorination with zinc/HOAc
afforded the corresponding cephalotaxus esters 1 (R ≠ H) or
their analogues with high yields (up to 94%) and
diastereoselectivities (dr up to 97:3) (Scheme 1). To the best
of our knowledge, this is the first report of highly stereo-
selective installation of the chiral oxygen-containing tetrasub-
stituted tertiary carbon stereocenter of the side chains of
cephalotaxus esters.
92
97:3
a
Reactions were performed on a 0.5 mmol scale at a 2a/3 ratio of
b
1:1.5 with 2.2 equiv of Lewis acid in 3 mL of CH2Cl2. Yields are for
combined isolated diastereomers. Absolute stereochemistry was
determined by independent synthesis (see the Supporting Informa-
tion). Crude product ratios were determined by HPLC (Chiralcel
AD-H column). The value in parentheses is the conversion rate. The
dr was determined after desilylation. The dr was determined after
dechlorination.
c
d
e
f
g
and 2). When the amount of BF3·Et2O was less than 1 equiv,
no identifiable product was obtained (see the Supporting
Information), whereas conversion of 2a was complete when the
amount of BF3·Et2O exceeded 2 equiv. Ketene silyl acetal 3b,
which has a bulky TBS group, gave a higher yield (80%) and
higher diastereoselectivity (75:25) than 3a. Lowering the
reaction temperature from −20 to −60 °C (entries 3 and 4)
dramatically increased the yield (95%) but did not significantly
improve the diastereoselectivity (80:20). Other Lewis acids,
including TiCl4, SnCl4, and ZnBr2, were evaluated (entries 5−
7) and found to exhibit low catalytic activities. Furthermore,
when the results were compared to those achieved with BF3·
Et2O, inverse selectivities were observed (entries 5 and 6).
Because the bulky TBS group of 3b resulted in high
diastereoselectivity, we also evaluated 3c, which has an α-
TMS group. Owing to the low reactivity of 3c, the reactions
were performed at higher temperatures (0 and −20 °C).
Compound 1b was obtained with excellent diastereoselectivity
(>99:1) but in low yields (entries 8 and 9). Next, we evaluated
α-chloride ketene silyl acetal 3d instead of 3c, knowing that the
chlorine atom in the resulting product 4a could be easily
removed by reduction with powdered Zn in HOAc. The
reaction of 2a with 3d at −40 °C for 12 h yielded 4a and three
diastereomers (drs) in a 68.6:27.4:2.8:1.2 ratio (see the
Supporting Information). Treatment of crude 4a and
corresponding drs with Zn/HOAc furnished 1b in 90% yield
with 96:4 diastereoselectivity (entry 10). Lowering the reaction
Initially, we selected α-ketoester 2a, which has an isopentyl
moiety and is a precursor to deoxyharringtonine (1b), as a
model substrate. α-Ketoester 2a was allowed to react with
various ketene silyl acetals in the presence of BF3·Et2O (2.2
equiv) as a Lewis acid catalyst in CH2Cl2 at −20 °C. After
B
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temperature to −60 or −78 °C slightly increased both the yield
and diastereoselectivity (entries 11 and 12). In summary, the
incorporation of a readily removable chlorine substituent to the
α-position of the ketene silyl acetal substantially increased the
yield and diastereoselectivity of the reaction, providing an
efficient method for stereoselectively installing the chiral
oxygen-containing tetrasubstituted tertiary carbon stereocenter
of the cephalotaxus ester side chains.
and 1j with high diastereoselectivities (entries 5 and 6). β-Aryl-
substituted α-ketoesters 2i and 2j, which have p-methyl and p-
methoxy groups, respectively, on their phenyl rings, were also
good substrates for this transformation. These substrates
showed high reactivity, providing corresponding products 1m
and 1n with dr values of 94:6 and 95:5, respectively (entries 9
and 10). Substrates with a m-methoxy group, that is, 2k and 2l,
afforded products 1o and 1p, respectively, with dr values of
95:5 and 97:3; however, these reactions were sluggish and
provided slightly lower yields (88% and 90%) and low
conversions (66% and 50%) even after reaction for 24 h
(entries 11 and 12).
Several α-ketoesters 2 derived from 1a were allowed to react
with 3d under the optimized reaction conditions, and the
results are summarized in Table 2. Variation of the alkyl group
To demonstrate the practical application of this efficient new
protocol, we selected homoharringtonine (1d) as a target
molecule and performed a multigram-scale synthesis (Scheme
2, a). The reaction of crude 2f (synthesized from 5 g of
Table 2. Mukaiyama Aldol Reactions of α-Ketoesters 2 with
3d
a
Scheme 2. Multigram Scale Synthesis of 1d and Conversions
of 1h to Other Cephalotaxus Esters
cephalotaxine) with 3d under the optimized reaction conditions
and subsequent dechlorination with Zn/HOAc in a one-pot
fashion yielded crude product 1j in 68% yield. Hydroxylation of
1j with 40% aqueous HBr at −15 °C for 12 h followed by
treatment with NaHCO3 for 5 h at room temperature afforded
1d in 90% yield with 93:7 diastereoselectivity. Recrystallization
from ethyl ether afforded 4.2 g (80%) of 1d with improved
diastereoselectivity (>99:1). Thus, homoharringtonine (1d)
was enantioselectively synthesized on a multigram scale from
cephalotaxine (1a) in 60% overall yield via five steps.
We also converted product 1h to other cephalotaxus esters
(Scheme 2, b). Protodesilylation of 1h with Et3N·3HF in
CH3CN at 80 °C for 3 d yielded harringtonine (1e) in 92%
yield. In contrast, treatment of 1 h with BF3·Et2O in CH2Cl2 at
room temperature for 4 h resulted in desilylation and
subsequent cyclization to afford anhydroharringtonine (1g) in
95% yield.
To elucidate the rational for the high diastereoselectivities of
the reactions of α-ketoesters 2 with ketene silyl acetal 3d, we
obtained X-ray crystal structures of 2a and the major aldol
product 4a (Figure 2). Based on these crystal structures and
references,13b,15 we propose the following explanation for the
stereochemistry of the reactions. The Lewis acid BF3·Et2O
activates the keto group of 2, and ketene silyl acetal 3d
approaches 2a from the Re face to yield 4a preferentially due to
a
Reaction conditions were the same as those described in Table 1,
b
entry 11. The dr values of crude products were determined by HPLC.
c
The value in parentheses is the conversion.
of 2 had little effect on the yield. Changing the R group from
isopentyl (2a) to isobutyl (2b) slightly decreased the
diastereoselectivity: nordeoxyharringtonine (1c) was obtained
with 90:10 diastereoselectivity (entry 2). Substrates with a
phenyl ring at the terminus of the R group, 2c and 2h, provided
homoneoharringtonines 1f and 1l, respectively, with 95:5
diastereoselectivity (entries 3 and 8). A substrate with an n-
pentyl group (2g) afforded 1k with a yield (92%) and
diastereoselectivity (dr = 92:8) comparable to those obtained
with 2a (compare entries 7 and 1). α-Ketoester 2d, which has a
tert-butyldimethylsilyl-protected hydroxyl (TBSO) group and is
a precursor to harringtonine (1e), also reacted smoothly with
3d to yield 1h with good to high diastereoselectivities (entries
4). Olefin-containing α-ketoesters 2e and 2f, which are
precursors to deoxyharringtonine (1b) and homodeoxyharring-
tonine or homoharringtonine (1d), respectively, provided 1i
C
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Letter
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Figure 2. Proposed explanation for the observed stereoselectivity.
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aldol reaction involving alkaloid 1a as a chiral auxiliary as an
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00743.
Experimental and characterization data, including 1H and
13C NMR spectra for all new compounds, chiral HPLC
spectra for the products, and crystallographic data (PDF)
X-ray data for compound 2a (CIF)
X-ray data for compound 1d (CIF)
X-ray data for compound 1e (CIF)
(12) (a) Chen, M.; Fang, J. J. Chem. Soc., Perkin Trans. 1 1993, 1737.
(b) Akiyama, T.; Ishikawa, K.; Ozaki, S. Synlett 1994, 1994, 275.
(c) Evans, D. A.; Trotter, B. W.; Barrow, J. C. Tetrahedron 1997, 53,
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(e) Aggarwal, V. K.; Masters, S. J.; Adams, H.; Spey, S. E.; Brown, G.
R.; Foubister, A. J. J. Chem. Soc., Perkin Trans. 1 1999, 155. (f) Loh, T.;
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(b) Brazeau, J.; Guilbault, A.; Kochuparampil, J.; Mochirian, P.;
Guindon, Y. Org. Lett. 2010, 12, 36.
X-ray data for compound s-2-A (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chenliyss@nankai.edu.cn.
ORCID
(14) The NMR spectroscopic data and the optical rotation ([α]D20
−122 (c 0.6, CHCl3), lit.6 [α]D26 −119 (c 0.6, CHCl3)) of the isolated
major isomer were identical to those reported for the natural product
(see refs 6 and 9a).
Li Chen: 0000-0001-8820-1496
(15) (a) Mahrwald, R. Chem. Rev. 1999, 99, 1095. (b) Lee, J. M.;
Helquist, P.; Wiest, O. J. Am. Chem. Soc. 2012, 134, 14973.
Author Contributions
§P.-F.L. and G.-Z.M. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21272126) and the Natural Science Foundation of Tianjin
(10JCYBJC04200) for financial support. Prof. Jian-Hua Xie of
Nankai Univeristy is greatly acknowledged for helpful
discussions.
D
DOI: 10.1021/acs.orglett.7b00743
Org. Lett. XXXX, XXX, XXX−XXX