Catalytic asymmetric synthesis of complex polypropionates: lewis base catalyzed aldol equivalents in the synthesis of erythronolide B

Article abstract of DOI:10.1002/anie.200906245

"Chemical Equation Presented" Powerful aldol reactions: Stereoselective Lewis base catalyzed aldol equivalents expediently provided eight of the ten stereocenters required for the synthesis of erythronolide B. Indeed, all eleven stereocenters present in the erythromycin aglycone have been derived directly or indirectly from catalytic asymmetric equivalents of aldol addition reactions (see scheme).

Full text of DOI:10.1002/anie.200906245

Angewandte
Chemie
DOI: 10.1002/anie.200906245
Asymmetric Synthesis
Catalytic Asymmetric Synthesis of Complex Polypropionates:
Lewis Base Catalyzed Aldol Equivalents in the Synthesis of
Erythronolide B**
Binita Chandra, Dezhi Fu, and Scott G. Nelson*
The complex stereochemical relationships and promising
biological activity characterizing many members of the
polyketides have spawned a wealth of reaction processes
designed to facilitate the asymmetric synthesis of these
natural products.[1] Among these natural products, the
erythromycins have attracted special attention as test cases
for evaluating these methodologies within the context of
total synthesis.[2] Accordingly, we were attracted to eryth-
ronolide B as a model for developing a catalytic asymmet-
ric synthesis of stereodefined polypropionate units that are
suitable for complex molecule synthesis. Towards this goal,
catalytic asymmetric ketene–aldehyde [2+2] cycloaddi-
tions serve as surrogates for asymmetric aldol additions
and provide a general strategy for the catalytic asymmetric
synthesis of complex polypropionate units.[3] An asymmet-
ric formal synthesis of erythronolide B (1) represents a
model, which illustrates the utility of catalytic asymmetric
transformations to directly or indirectly establish each of
the ten stereogenic centers found in the erythromycin
aglycone. (Scheme 1).
Ketene–aldehyde cycloadditions represent surrogates
for catalytic asymmetric aldol additions by exploting
Scheme 1. Catalytic asymmetric synthesis of erythronolide B. TMS=trime-
thylsilyl, Pg=protecting group.
ketenes as enolate equivalents.[4] Extrapolation of this
reaction design towards a strategy for catalytic asymmetric
synthesis of polypropionates implicates iterative catalyst-
controlled coupling of methylketene units as the means for
chain elongation of the propionate unit. A synthesis of
erythronolide B predicated on this analysis emerges by
6 to mediate a highly Felkin-selective Mukaiyama aldol
homologation.
ꢀ
ꢀ
disconnecting the aglycone across the C1 O13 and C7 C8
bonds to reveal two modified propionate trimer equivalents 2
and 3. The syn,anti,syn synthon 2 correlates to sequential
catalyst-controlled methylketene coupling with propionalde-
hyde using the alkaloid catalysts 4 and 5. The all-syn synthon 3
would be derived from the alkaloid-catalyzed cyclocondensa-
tion of methacrolein with methylketene; ensuing homologa-
Synthesis of the C8–C15 synthon 2 commenced with the
cyclocondensation of propionyl chloride with propionalde-
hyde catalyzed by O-trimethylsilylquinidine (4) and provided
ꢀ
b-lactone 7, which represents the C12 C13 syn-propionate
unit (74%, 98% ee, ꢁ 98% de; Scheme 2).[4b] Lactone 7 was
then modified to allow further propionate chain elongation by
its conversion into the b-hydroxy aldehyde 8 through a two-
step sequence: 1) thiolate-mediated ring opening and in situ
alkoxide silylation; 2) DIBAL-mediated thioester reduction
(86% for 2 steps). Further homologation of 8 with methyl-
ketene, now using the quinine-based catalyst 5, provided the
targeted propionate trimer equivalent with syn,anti,syn link-
age in the form of b-lactone 9 (95%, > 95% de). The
conversion of b-lactone 9 into ethyl ketone 11 was carried
out by employing N,O-dimethylhydroxylamine, which medi-
ated the b-lactone ring opening, and subsequent EtMgBr
addition to the derived amide 10 afforded the ethyl ketone
11.[5] Conversion of the hydroxyl group at C11 into the PMB
ether was best accomplished using (p-methoxybenzyl)tri-
chloroacetimidate and a substoichiometric amount of the
ꢀ
tion of the resulting C6 C7 syn-propionate unit would exploit
simple substrate-based stereocontrol utilizing achiral catalyst
[*] B. Chandra, D. Fu, Prof. S. G. Nelson
Department of Chemistry, University of Pittsburgh
Pittsburgh, PA 15260 (USA)
Fax: (+1)412-624-8611
E-mail: sgnelson@pitt.edu
Homepage: http://www.sgnpittchemistry.com
[**] Generous support from the National Institutes of Health
(NIGMS R01 GM063151) is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200906245.
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considered the potential for Lewis base catalyzed variants
to provide the requisite aldol diastereoselectivity.[10] Given
the paucity of data regarding the applicability of Lewis base
catalysis to diastereoselective Mukaiyama aldols, our initial
investigations were directed towards establishing the val-
idity of this reaction design.
Thus, we evaluated the stereochemical outcome of
Lewis base catalyzed enol silane additions to chiral a-
substituted aldehydes. The results revealed that acyl-
pyrrole-derived enol silanes in combination with phenox-
ide-based catalysts delivered all-syn selective aldol adducts.
Aldehyde 12a (R = (CH2)2Ph) and enol silane 14a were
treated with tetra-n-butylammonium p-nitrophenoxide
(20 mol% of catalyst 6 was used)[11] and afforded the all-
syn propionate trimer 15 with high diastereoselectivity (15/
16 = 98:2; Table 1, entry 2). The efficient silyl-group trans-
fer from the enolate group to the emergent aldolate oxygen
atom accompanied the aldol addition (Table 1, entry 1).
Control experiments revealed that p-nitrophenoxide pos-
sesses the correct Lewis basicity to promote efficient enol
silane addition without affecting base-promoted epimeri-
Scheme 2. Synthesis of the C8–C15 synthon 2. Reagents and conditions:
a) 4 (10 mol%), EtCOCl, iPr2NEt, LiClO4, ꢀ788C; b) EtSH, KHMDS
(10 mol%), THF; TBSOTf, 2,6-lutidine; c) DIBAL, CH2Cl2, ꢀ788C; d) 5
(10 mol%), EtCOCl, iPr2NEt, LiI, ꢀ788C; e) MeO(Me)NH2Cl, Me2AlCl,
CH2Cl2; f) EtMgBr, THF; g) PMBOC(NH)CCl3, BF3·Et2O (15 mol%),
CH2Cl2. DIBAL=diisobutylaluminum hydride, HMDS=hexamethyldisila-
zane, PMB=p-methoxybenzyl, TBS=tert-butyldimethylsilyl, THF=tetrahy-
drofuran, Tf=trifluoromethanesulfonyl.
Table 1: Phenoxide-catalyzed aldol additions of N-acyl pyrrole-derived
enol silanes, see [Eq. (1)].
Lewis acid BF3, thus affording the completed C8–C15 frag-
ment 2 (52% yield over 7 steps).[6]
Despite the close structural homology that exists between
synthons 2 and 3, the all-syn relative configuration present in
3 suggested a complementary strategy for propionate assem-
bly relative to that employed for the completion of 2.
Entry 12, R[a]
Enol silane Catalyst[b]
X
15/16
(yield [%])[c]
1
2
3
4
5
6
12a,C(CH2)Me 14a
12b,CH2CH2Ph 14a
6
6
BF3
BF3
6
NC4H4 99:1 (73)
NC4H4 98:2 (80)
NC4H4 83:17 (66)
[d]
[d]
Cinchona-alkaloid-catalyzed
methylketene–methacrolein
12b
12b
12b
12b
14a
14b
14b
14c
StBu
–
–
50:50 (68)
n.r.
coupling would provide uneventful access to the requisite
ꢀ
C4 C5 syn building block 12. We reasoned that securing
6
n.r.
rigorous Felkin facial control in the enolate additions to 12,
ideally via open transition state 13, would deliver the
necessary all-syn unit without the intervention of chiral
catalysts or auxiliary stereocontrol devices [Eq. (1)].[7] Liter-
ature precedent, however, suggested that oxazolidinone-
derived enolates provide the method of choice for accessing
all-syn dipropionate units, thus indicating that simple alde-
hyde-based diastereoselection is insufficient for achieving
high Felkin selectivity.[8]
[a] R3Si=TMS (entry 1) or TBS (entries 2–6). [b] Catalyst (20 mol%) was
used except as noted. [c] Diastereomer ratios were determined by GC
analysis (see the Supporting Information). [d] BF3·OEt2 (1.0 equiv).
n.r.=no reaction
zation of the a-substituted aldehydes. Reaction efficiency was
eroded significantly using the stoichiometric quantities of
boron trifluoride required to achieve complete conversion
(Table 1, entries 4 and 5). Similarly, enol silane 14a
exhibited unique reactivity in the phenoxide-catalyzed
aldols, as the ketene acetal 14b and ketone-derived enol
silane 14c were not compatible reaction partners (Table 1,
entries 5 and 6).
Next, assembly of the C1–C7 subunit 3 was investigated,
and began with the cyclocondensation of propionyl chlo-
ride with methacrolein catalyzed by O-trimethylsilylqui-
nine (5), thus affording the volatile b-lactone 17 (62%,
98% ee, syn/anti ꢁ 98:2; Scheme 3). Conversion of the b-
lactone into the aldehyde was again accomplished by the
thiolate-ring opening/thioester reduction sequence, and
afforded syn aldehyde 18 (89% over 2 steps).Homologating
18 with enol silane 14a (20 mol% of catalyst 6 was used)
afforded, after acidic work-up, the all-syn aldol adduct 19
(78%, d.r. 99:1). The crucial role played by cyclic ketal
protecting groups in facilitating eventual seco-acid macro-
The preceding analysis suggested that Mukaiyama-type
aldol reactions could be candidates for accessing the requisite
Felkin facial bias from enolate additions to a-substituted
aldehydes.[9] Considering that Lewis acid mediated
Mukaiyama aldol reactions afforded modest diastereoselec-
tivity in the homologations of syn-disubstituted aldehydes, we
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concomitant installation of a tertiary alcohol at C6. To this
end, oxidative cleavage of the alkene group preceded Felkin-
selective vinyl Grignard addition to the resulting methyl
ketone, which delivered tertiary alcohol 21 (99%, 100% de;
Scheme 4).[13] Unveiling the newly installed terminal olefin as
the corresponding aldehyde, and protection of the tertiary
alcohol, completed the C1–C7 synthon in the from of
aldehyde 3.
Coupling fragments 2 and 3 to secure the erythronolide
carbon framework was predicated on correctly establishing
the unaddressed C8 stereocenter (Scheme 5). To this end, the
kinetic Z-lithium enolate of ethyl ketone 2 was treated with
aldehyde 3, and afforded b-hydroxy ketone 22 as a single syn-
aldol diastereomer (55%; 90% based on recovered 2).[14]
Successful fragment coupling was dependent on quenching
the incipient aldolate intermediate 23 with a soluble proton
source (AcOH) at low temperature; warming the aldolate or
attempted quenching using aqueous solutions at low temper-
ature led to silyl-group migration and irreversible formation
of lactol 24. Hydroxy-directed reduction of the ketone
(ꢁ97% de) delivered the S alcohol at C9, and allowed the
PMB ether at C11 to be engaged as the C9–C11 p-anisyl
acetal 25 (98% over 2 steps).[15] Deoxygentaion of the alcohol
at C7 was carried out using the conditions developed by
Evans et al., providing that formation of xanthate 26 was
achieved at low temperature (ꢀ788C) to circumvent the
aforementioned silyl-group migration.[14b,16] Deoxygenation
was accompanied by epimerization of the acetal stereocenter
(ca. 2.4:1), thus necessitating that the desired configuration be
re-established from the crude mixture of diastereomers (4-
MeOC6H4CH(OMe)2, H+) to secure 27 (68% over 3 steps).
Ester saponification, removal of the silyl ether, and subse-
quent macrolactonization using modified Yamaguchi condi-
tions,[17] afforded the protected (9S)-dihydroerythronolide B
28 (78% over 3 steps). Macrolactone 28 represents the
completion of our formal synthesis, as this same material had
Scheme 3. Synthesis of all-syn propionate trimer 20. Reagents and
conditions: a) 5 (10 mol%), iPr2NEt, LiI, ꢀ408C; b) EtSH, KHMDS
(10 mol%), THF; TBSCl and Et3N; c) DIBAL, CH2Cl2, ꢀ788C; d) 14a,
6 (20 mol%), THF, ꢀ708C; then 1n HCl; e) Me2C(OMe)2, CSA
(0.05 mol%); f) NaOMe, MeOH, 08C. CSA=camphorsulfonic acid.
lactonization requires that diol 19 be engaged as the
corresponding cyclic dimethyl ketal.[12] Potential incompati-
bility of the electron-rich pyrrole ring with ensuing oxidative
reaction conditions dictated that the acyl pyrrole group would
be transformed into methyl ester 20 in advance of completing
the C1–C7 unit (83% over 2 steps).
At this juncture, completion of the C1–C7 synthon
necessitated a one carbon chain homologation of 20 with
Scheme 4. Synthesis of the C1–C7 synthon 3. Reagents and condi-
tions: a) O3, CH2Cl2, ꢀ788C; then Me2S; b) CH2CHMgBr, THF,
ꢀ788C; c) TESOTf, 2,6-lutidine. TES=triethylsilyl.
Scheme 5. Fragment coupling and macrolide construction. Reagents and conditions: a) LiHMDS, THF, ꢀ788C, 3; then AcOH, ꢀ78!238C; b) Zn(BH4)2,
Et2O; c) DDQ, CH2Cl2; d) KHMDS, CS2, MeI, ꢀ788C; e) AIBN, nBu3SnH; f) 4-MeOC6H4CH(OMe)2, CSA (0.05 mol%); g) LiOH, THF/MeOH (1:1) , 558C;
h) (nBu)4NF, THF, 658C; i) 2,4,6-(Cl3C6H2)COCl, DMAP, Et3N, C6H6. AIBN=azabis(isobutyro)nitrile, DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone,
DMAP=4-dimethylaminopyridine, pAn=p-anisyl. For the conversion of 28 into 1 see Ref. [18].
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Communications
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Lewis base catalyzed aldol equivalents provide direct
access to eight, and indirect access to the remaining three of
the eleven stereocenters, which render erythronolide B an
enduring test case for asymmetric synthetic methods. This
formal synthesis of erythronolide B highlights the efficient
access to complex polypropionate architectures, which are
afforded by asymmetric catalysis using easily obtained,
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[11] H. Fujisawa, Y. Nagata, Y. Sato, T. Mukaiyama, Chem. Lett.
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Received: November 5, 2009
Published online: March 4, 2010
Keywords: aldol reaction · asymmetric synthesis ·
.
homogeneous catalysis · cycloaddition · natural products
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