Synthesis of bioactive natural products by asymmetric syn-and anti-aldol reactions

Article abstract of DOI:10.1055/s-0029-1216941

The use of several variants of the asymmetric aldol reaction as key steps in the syntheses of bioactive target molecules is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1216941

2992
PAPER
Synthesis of Bioactive Natural Products by Asymmetric syn- and anti-Aldol
Reactions
Asymmetric
A
ldol
r
Reactio
u
ns n K. Ghosh,* Zachary L. Dawson
Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA
Fax +1(765)4961612; E-mail: akghosh@purdue.edu
Received 23 June 2009
tion, and a nitro-aldol reaction.3 We will also describe a
Abstract: The use of several variants of the asymmetric aldol reac-
tion as key steps in the syntheses of bioactive target molecules is de-
scribed.
recent asymmetric reductive aldol process developed in
our laboratory in the context of the synthesis of peloruside
A, a potent anticancer agent with clinical potential.4,5 Fur-
thermore, we report an asymmetric aldol-based synthesis
of a stereochemically defined bis-tetrahydrofuran (bis-
THF) scaffold present in ginkolide natural products.6 This
scaffold has been successfully incorporated in the design
and development of Darunavir, a HIV-1 protease inhibitor
for the treatment of multi-drug-resistant HIV-1 variants
that has recently been approved by the US Food and Drug
Administration (FDA).
Key words: natural products, asymmetric synthesis, chiral auxilia-
ry, syn-aldol, anti-aldol, indanolamine
For centuries, natural products have been a major source
of inspiration to researchers in the fields of chemistry, bi-
ology, and medicine. Numerous natural products and their
derivatives have received approval as front-line therapies
for the treatment of a variety of human diseases. The
seemingly endless structural diversity, complexity, and
important biological functions of natural products have
provided an impetus for the development of novel meth-
odologies for their synthesis. Furthermore, drug-discov-
ery researchers frequently attempt to reproduce various
structural motifs and stereochemically defined functional-
ities from natural products. This has further stimulated the
design and development of new and practical synthetic
technologies, and has greatly enhanced medicinal re-
search investigations in academia and industry.
Hapalosin
Multi-drug resistance (MDR) is a phenomenon whereby
many cancers develop resistance to chemotherapeutic
drugs, and it is a major factor for treatment failure. It ap-
pears that MDR is caused by overexpression of P-glyco-
protein, a 170–200 kDa transmembrane protein that acts
as an ATP-dependent drug efflux pump.7 Hapalosin (1),
isolated from the blue-green alga Hapalosiphon
welwitschii,8 has shown a reversing effect on MDR in tu-
mor cells.9 We reported the first total synthesis of hapa-
losin in 1996. In this synthesis, we used Evans’s
asymmetric syn-aldol reaction to install two key stereo-
centers.10 This aldol strategy involved the use of an
aminoindanol-based chiral oxazolidinone as the chiral
auxiliary. As shown in Scheme 1, the reaction of oxazoli-
dinone 911 and octanal with dibutylboryl triflate and tri-
ethylamine at –78 °C gave the aldol adduct 10 in 90%
yield. The resulting aldolate was protected as its tetrahy-
dropyranyl ether, and the chiral auxiliary was removed to
give the corresponding acid. Coupling of this acid with al-
cohol 11 gave diester 12. The tetrahydropyranyl group
was removed and the diester was coupled with acid 13 to
provide the corresponding ester. Removal of the benzyl
and benzyloxycarbonyl protecting groups, followed by cy-
cloamidation of the resulting amino acid 14 with N-ethyl-
N¢-(3-dimethylaminopropyl)carbodiimide and N-hydrox-
ybenzotriazole afforded the corresponding cycloamide.
Removal of the methoxymethyl protecting group then
gave synthetic hapalosin.
Over the years, we have been involved in the synthesis of
a range of structurally diverse natural products with a va-
riety of biological activities. Our objectives have been to
synthesize these scarce natural products efficiently, to car-
ry out further biological evaluation, to perform structure–
activity studies, and to prepare structural variants for bio-
logical studies. In this context, we have developed a vari-
ety of methods for asymmetric synthesis, including highly
diastereoselective syn- and anti-aldol reactions that rely
on ester-derived titanium enolates.
The aldol reaction is one of the most powerful reactions
for forming carbon–carbon bonds that is available in or-
ganic synthesis. Asymmetric aldol reactions have proved
their versatility and utility in organic synthesis, especially
for the construction of architecturally complex natural
products. Here we report our attempts to use the asymmet-
ric aldol reaction as a key step in the synthesis of a variety
of bioactive target molecules (Figure 1). In these studies,
we used several asymmetric aldol reactions, including
Evans’s syn-aldol protocol,1 Mukaiyama’s aldol reac-
tion,2 our own chiral ester-based asymmetric aldol reac-
(+)-Cryptophycin B
The synthesis of cryptophycins, which are a group of ma-
rine depsipeptides isolated from Nostoc sp., has attracted
much attention over the years because of the significant
clinical potential of these chemicals and their relatively
low natural abundance.12 Members of the cryptophycin
SYNTHESIS 2009, No. 17, pp 2992–3002
x
x.
x
x
.
2
0
0
9
Advanced online publication: 14.08.2009
DOI: 10.1055/s-0029-1216941; Art ID: C02809SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Asymmetric Aldol Reactions
2993
Me
O
O
H
H
O
Me
Me
O
O
O
HN
N
O
O
O
HO
O
N
H
O
OMe
Me
O
(+)-cryptophycin B (2)
hapalosin (1)
OH
O
H
N
OHC
O
O
OH NH2
O
H
N
CO2H
O
O
O
OH
microbial agent AI-77-B (4)
OH
(–)-tetrahydrolipstatin (3)
OH
O
H
Me
HN
O
Me
O
O
O
O
Me
H
HN
O
O
N
Me
Me
Br
Me
Me
NH
Me
(+)-amphidinolide T1 (5)
O
Me
(+)-jasplakinolide (6)
Me
O
OMe
O
O
O
Me
O
HO
1
NH
11
OH
HO
Me
HO
O
O
N
OMe
O
Me
MeO
OH
Me Me
(+)-peloruside A (7)
stereocalpin A (8)
(proposed structure)
Figure 1 Some natural products synthesized by aldol reaction strategies
family, including arenastatin, inhibit tubulin polymeriza- ing methyl group was accomplished in a one-pot, two-step
tion in vitro, which may render these compounds or their sequence to give the alcohol intermediate 17. This was
derivatives important in cancer therapy.13
converted into the corresponding aldehyde followed by a
Horner–Wadsworth–Emmons reaction with ethyl (di-
ethoxyphosphono)acetate to give ester 18. This acid was
coupled with tert-butyl O-methyl-D-tyrosinate to afford
amide 19, which was then attached to the protected amino
acid 20 by means of Yamaguchi coupling. Macrolactam-
ization of the amino acid derived from the resulting deriv-
ative 21 was accomplished by using Yamaguchi’s
protocol. Epoxidation with dimethyldioxirane gave the ti-
tle compound as a 3:1 mixture of epoxides. We have since
carried out a synthesis of cryptophycin-52 by a non-aldol
process.15
We carried out a convergent synthesis of cryptophycin B
(2) by using aldol reactions based on asymmetric titanium
enolates that we developed in our laboratory.14 As shown
in Scheme 2, ester 15, obtained by coupling (3E)-4-phe-
nylbut-3-enoic acid and 1-(N-tosylamino)indan-2-ol, was
treated with titanium tetrachloride and N,N-diisopropyl-
ethylamine. The resulting enolate was treated with 3-(ben-
zyloxy)propanal to provide the syn-aldol adduct 16 in
98% yield as a single diastereomer. Reduction of the aldol
adduct with lithium aluminum hydride and selective con-
version of the primary hydroxy group into the correspond-
Synthesis 2009, No. 17, 2992–3002 © Thieme Stuttgart · New York

2994
A. K. Ghosh, Z. L. Dawson
PAPER
O
O
OH
O
O
Ts
Ts
Bu2BOTf
Et3N
NH
NH
O
O
OH
TiCl4
DIPEA
C7H15
N
O
N
O
C7H15CHO
Me
O
O
BnO
O
16
15
10
(90%)
9
Ph
Ph
Bn
CHO
(98%)
steps
O
Ph
O
HO
O
OH OBn
OTIPS
11
Me
Me
CO2Et
THP
O
17
O
18
O
12
C7H15
Ph
Ph
steps
O
Ph
Me
Me
N
OMOM
CO2H
Me
H
N
Cbz
Ph
13
OH
O
Ph
O
19
O
O
OMe
H
COOH
NH
HO
O
O
Me
t-Bu
Me
O
steps
Boc
hapalosin (1)
Ph
RO
O
N
H
O
O
H
Me
20
Me
14 R = MOM
O
Ph
Scheme 1 Synthesis of hapalosin
O
O
O
HN
Me
O
O
O
OMe
(–)-Tetrahydrolipstatin
HN
steps
(–)-Tetrahydrolipstatin (3), a saturated derivative of lip-
statin, was isolated in 1987, from the bacterium Strepto-
myces toxytricini.16,17 This compound, under the trade
name Xenical®, has been approved by the FDA as an anti-
obesity agent. It inhibits pancreatic lipase by irreversibly
binding to the serine at the active site with its b-lactone
moiety.17 We synthesized tetrahydrolipstatin using an
asymmetric ester-derived titanium enolate anti-aldol reac-
tion and a nitro-aldol reaction as key steps.18
Boc
21
cryptophycin B (2)
Scheme 2 Synthesis of cryptophycin B
group gave the triisopropylsilyl ether 28. The synthesis of
tetrahydrolipstatin was completed by treating acid 28 with
benzenesulfonyl chloride in pyridine at 0 °C to give the b-
lactone and then removal of the triisopropylsilyl ether and
Mitsunobu esterification with N-formyl-L-leucine.
Chiral ester 22, was treated with titanium tetrachloride
and N,N-diisopropylethylamine in dichloromethane at
0 °C to 23 °C. The resulting enolate was then cooled to
–78 °C and trans-cinnamaldehyde complexed with dibu-
tylboryl triflate (premixed) was added to give the anti-al-
dol product 23 in 60% yield (6.1:1 dr). This aldol product
was converted into the aldehyde 24. A nitro-aldol reaction
of aldehyde 24 with nitrododecane in N,N-dimethylform-
amide containing a catalytic amount of tetrabutylammoni-
um fluoride provided the nitro-aldol product 25 in 82%
yield as a mixture of diastereomers. After dehydration of
the nitro-aldolate, the resulting nitrovinyl moiety was con-
verted into the corresponding oxime, which was reduced
to give ketone 26 as a single isomer. The dioxanone was
hydrolyzed under Seebach’s conditions,19 and the result-
ing b-hydroxy acid was protected as a benzyl ester. The
resulting ketone was reduced by using an anti-selective
reduction protocol developed by Evans (selectivity
22:1).20 Selective protection of the less hindered hydroxy
Pseudopeptide Microbial Agent AI-77-B
AI-77-B (4) was isolated from the fermentation broths of
Bacillus pumilus AI-77 in 1982.21 It has unique gastropro-
tective properties with few side effects; however, its ther-
apeutic potential has been limited because of its poor oral
absorption properties.22 We synthesized the compound by
using a titanium enolate-mediated syn-aldol reaction to
generate the dihydroxyamino acid moiety.23 Other key re-
action steps of our synthesis include a Curtius rearrange-
ment, a regioselective Diels–Alder reaction, and a
Dondoni homologation.
Chiral ester 29 was treated with titanium tetrachloride and
N,N-diisopropylethylamine in dichloromethane at room
temperature to give the corresponding titanium enolate,
which was cooled to –78 °C and treated with (benzyl-
oxy)acetaldehyde. The resulting aldol adduct 30 was iso-
lated as a single diastereomer in 97% yield. The chiral
Synthesis 2009, No. 17, 2992–3002 © Thieme Stuttgart · New York

PAPER
Asymmetric Aldol Reactions
2995
lide T1 utilizing diastereoselective aldol reactions, an
oxocarbenium ion-mediated alkylation, cross-metathesis,
and a novel exo-methylene group protection as the key
steps.28
Ts
Ts
NH
NH
O
O
OH
TiCl4
DIPEA
O
O
Ph
H13C6
H13C6
Ph
Aldol adduct 38 was generated from the condensation of
the 1-(N-tosylamino)indan-2-ol ester 37 with 3-(benzyl-
oxy)propanal (Scheme 5). The aldol adduct was obtained
as a single diastereomer in 90% yield. Removal of the
chiral auxiliary with lithium aluminum hydride gave the
corresponding diol, which was converted into the g-lac-
tone 39 in three steps. Lactone 39 was, in turn, trans-
formed into alkene 40. Cross-metathesis of 40 and
oxazolidinone derivative 41 in the presence of Grubbs cat-
alyst gave a 1:1 mixture of the E- and Z-isomers of the
cross-coupled product 42. Sulfone 43 was obtained by
treating the corresponding benzyl ester derivative of 42
with benzenesulfinic acid and calcium chloride.
22
23
CHO
steps
O
O
TBAF
NO2
O
O
Me(CH2)11NO2
O
C11H23
O
CHO
DMF, 23 °C
OH
C6H13
C6H13
25
24
Scheme 6 outlines the synthesis of the C11–C22 segment
and the completion of the synthesis of amphidinolide T1.
Ester-enolate aldol reaction of ent-37 with (benzyl-
oxy)acetaldehyde gave the aldolate 44 as a single diaste-
reomer in 95% yield. This was readily converted into
O
O
O
O
OH
O
O
C11H23
BnO
C11H23
C6H13
C6H13
26
27
Ts
Ts
NH
NH
O
O
OH
O
OH
TiCl4
DIPEA
OTIPS
C11H23
steps
O
O
(–)-tetrahydro-
lipstatin (3)
HO
BnO
OBn
C6H13
29
30
CHO
28
Scheme 3 Synthesis of tetrahydrolipstatin
O
auxiliary was removed and the resulting acid was convert-
ed into oxazolidinone 31 by a Curtius rearrangement. Ox-
azolidinone 31 was converted into the tert-
butoxycarbonyl-protected acetonide 32. Benzyl deprotec-
tion and Swern oxidation gave an aldehyde that was sub-
jected to stereoselective homologation, as developed by
Dondoni and co-workers,24 to provide thiazole 33. This
thiazole was transformed into the corresponding alde-
hyde, which was oxidized to give the acid analogue 34.
Coupling of this acid with the isocoumarin fragment 35
provided amide 36.25 The terminal alkene group of amide
36 was oxidized to an acid and protected as its benzyl es-
ter, which allowed a clean O-demethylation of the aromat-
ic methoxy group. Removal of the protecting groups gave
AI-77-B (4).
O
O
OBn
OBn
N
Boc
HN
32
31
S
O
O
O
N
Boc
N
Boc
N
OH
OH
OBn
33
34
OMe
O
O
NH2
(+)-Amphidinolide T1
35
The Amphidinium species of marine dinoflagellates have
developed metabolites that are quite potent against a vari-
ety of cancer cell lines.26 The 19-membered amphidino-
lide T1, (5) has shown potent activity against murine
lymphoma L1210 and human epidermoid carcinoma KB
cell lines.27 As a result of their low natural abundance,
high biological activity, and unique structural features, the
amphidinolides have attracted much attention and have
been the subject of many synthetic and biological studies.
We accomplished the first total synthesis of amphidino-
OMe
O
steps
O
OBn
AI-77-B (4)
H
N
N
Boc
O
O
36
Scheme 4 Synthesis of the pseudopeptide microbial agent AI-77-B
Synthesis 2009, No. 17, 2992–3002 © Thieme Stuttgart · New York

2996
A. K. Ghosh, Z. L. Dawson
PAPER
Ts
The initial C2-stereocenter was created by an Evans syn-
aldol reaction, as shown in Scheme 7.1 The boron-enolate
of oxazolidinone 50 was treated with methacrolein at
–78 °C to 0 °C to give the aldol condensation product 51
in 94% yield. Allylic alcohol 51 was heated in 1,1,1-tri-
ethoxypropane at 140 °C in the presence of a catalytic
amount of propionic acid to yield the Claisen rearrange-
ment product, ester 52.36 Hydrolysis of the oxazolidinone
afforded a primary hydroxy group that was converted into
a nitrile group through a Mitsunobu reaction using ace-
tone cyanohydrin. The resulting nitrile was reduced with
Raney nickel catalyst to give aldehyde 53. Methyl Grig-
nard addition to aldehyde 53, silylation, and ester hydro-
lysis gave acid 54. The mixture of diastereomers resulting
from the Grignard reaction was readily separated, and the
undesired diastereomer was converted into the desired al-
cohol by a two-step procedure.
Ts
NH
NH
TiCl4
DIPEA
O
O
OH
O
O
O
BnO
Me
37
38
Bn
(90%)
CHO
TMS
O
O
H
H
H
H
Me
Me
O
O
40
39
Ph
OBn
Me
N
O
41
O
O
The b-tyrosine moiety was prepared by using chemistry
developed by Davis and co-workers.37 Coupling of amino
ester 55 and acid 56 gave the tripeptide 57 (Scheme 8).
Further coupling of acid 54 to tripeptide 57 gave ester 58.
Removal of the tert-butyl(dimethyl)silyl protecting group
and ester hydrolysis followed by Yamaguchi macrolac-
tonization gave the corresponding macrolactone. Subse-
quent removal of the phenolic triisopropylsilyl group gave
TMS
SO2Ph
O
H
H
H
Me
Me
O
O
Ph
H
Me
Me
OBn
O
N
O
O
43
O
42
Ts
Ts
Scheme 5 Synthesis of sulfone fragment 43
NH
NH
O
O
OH
TiCl4
DIPEA
O
O
iodide 45 by protecting the alcohol as a triisopropysilyl
ether, reduction with diisobutylaluminum hydride, and
conversion of the resulting alcohol into an iodide. Lithia-
tion of iodide 45 followed by reaction with aldehyde 46
gave a 1:1 mixture of alcohols, which were oxidized to
give a ketone that was converted into olefin 47 under
Petasis’s conditions.29 After reductive removal of the tri-
isopropysilyl and benzyl groups, the resulting diol was
treated with N-bromosuccinimide to give a bromotetrahy-
drofuran that was subsequently converted into enol ether
48. A modified procedure, first developed by Ley,30 was
used to carry out the key oxocarbenium ion-mediated
alkylation of segments 43 and 48 to give compound 49.
Deprotection of the coupled product 49 and subsequent
Yamaguchi macrolactonization gave the macrolactone,
which upon reductive unmasking of the bromoether gave
amphidinolide T1.
BnO
Me
OBn
44
ent-37
CHO
(93%)
OBn Me
OTBS
OTIPS
OBn
I
OTIPS
Me
45
47
OTBS
OHC
46
Me
Br
OTBS
O
Me
H
Br
48
OTBS
H
(+)-Jasplakinolide
H
O
Me
Jasplakinolide (6), a 19-membered cyclic depsipeptide,
has attracted the attention of many synthesis groups since
its isolation from the Fijian marine sponge Jaspis splen-
dens in 1986.31 Jasplakinolide has shown excellent antitu-
mor activity,32 and was a candidate for clinical
development until this was stopped as a result of the com-
pound’s toxicity.33 A number of syntheses of jasplakino-
lide have been reported.34 We recently reported a
convergent synthesis of this molecule. The polypropionic
acid segment was synthesized by using an aldol reaction
followed by a Claisen rearrangement as the key steps.35
O
O
43, DTBMP
TBSO
H
AlCl3, –35 °C
Me
OBn
49
O
amphidinolide T1 (5)
Scheme 6 Completion of the synthesis of amphidinolide T1;
DTBMP = 2,6-di-tert-butyl-4-methylpyridine
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PAPER
Asymmetric Aldol Reactions
2997
tic effect with taxol, arresting cells undergoing mitosis in
the G2-phase by binding to a nontaxoid region of tubu-
lin.39 Peloruside A represents a new class of antitumor
agents, and it has shown excellent potency against P388
murine leukemia cells (IC50 = 10 nM).40 The potency, in-
triguing structure, and potential clinical applications have
attracted much interest. Two total syntheses41 and several
synthetic studies on peloruside have been published.42,43
We have reported a convergent synthesis of peloruside A
that featured a novel aldol reaction mediated by L-Selec-
tride [lithium tri(sec-butyl)borohydride] as one of the key
steps.5
O
O
O
OH
O
Bu2BOTf
DIPEA
O
N
O
N
Me
methacrolein
–78 °C to 0 °C
51
50
Ph
(94%)
Ph
EtC(OEt)3
EtCO2H (cat.)
140 °C
O
O
O
OEt
O
N
Me
Me
Me
52
Ph
The synthesis of the C1–C10 segment is shown in
Scheme 9. Commercially available isopropylidene-D-
threitol (59) was converted into the isopropylidene prod-
uct 60. Acid-catalyzed removal of the isopropylidene
group followed by iodoesterification and subsequent O-
methylation gave iodide 61. This was then converted into
an aldehyde, which in turn was subjected to Brown’s
asymmetric allylation to give alcohol 62.44 Alcohol 62
was converted into diol 63 by using an Ando Z-
OTBS
Me
O
Me
Me
OEt
Me
54
HO
O
Me
Me
OHC
53
Me
Scheme 7 Synthesis of protected 8-hydroxynonenoic acid 54
olefination45
and
a
Sharpless
asymmetric
dihydroxylation46 as the key steps. The diol was then con-
verted into enone 64 by standard synthetic steps.
OTIPS
NH2
O
OMe
OPMB
OH
O
55
TIPSO
O
HN
OMe
O
HO
O
+
O
O
O
60
OH
59
HN
N
Me
steps
Br
O
57
NH2
HN
OPMB
OMOM
Me
N
O
Me
OPMB
Br
MeO
Me
NH
MeO
O
56
HO
Boc
61
62
OTIPS
I
OMe
PMBO
CO2Me
HN
MOMO
OTBS
TBSO
OMe
TBSO
O
O
O
Me
OEt
OPMB
OMOM
HN
Me
N
steps
Me
O
Br
O
OH
63
O
64
OH
Me
NH
Me
(+)-jasplakinolide (6)
O
Scheme 9 Synthesis of peloruside A intermediate 64
Me
58
Scheme 8 Completion of (+)-jasplakinolide
The completion of the synthesis of peloruside A is shown
in Scheme 10. The protected homoallylic alcohol 66 was
generated from chiral imide 65.43 The terminal olefin was
oxidized and exposed to asymmetric allylation conditions
to give a 5:1 mixture of diastereomers. The resulting alco-
hol was converted into a methyl ether, and oxidative
cleavage of the terminal alkene gave aldehyde 67. Treat-
ment of enone 64 with L-Selectride at –78 °C for 10 min-
utes, followed by addition of aldehyde 67, gave aldol
synthetic jasplakinolide. Structural modifications with the
goal of identifying less toxic and more potent derivatives
are currently in progress in our laboratory.
Peloruside A
The microtubule-stabilizing agent peloruside A (7) was
isolated from the marine sponge Mycale hentscheli in
2000.38 Like laulimalide, peloruside A shows a synergis-
Synthesis 2009, No. 17, 2992–3002 © Thieme Stuttgart · New York

2998
A. K. Ghosh, Z. L. Dawson
PAPER
adduct 68 as a 4:1 mixture of diastereomers in 92% yield. 1B (PTP1B) inhibitory activity.47 We recently carried out
We recently investigated the scope of this reaction for a a 14-step synthesis of the proposed structure of stereo-
variety of chiral and achiral enones and aldehydes. Our calpin A, which involved syn- and anti-aldol reactions as
exploration of this reductive aldol strategy showed that key steps.48
several representative aldol adducts can be prepared in
As shown in Scheme 11, in a titanium tetrachloride-pro-
good yield and high diastereoselectivity when the reactant
aldehyde contains an a-chiral center.4 The synthesis of
peloruside A was carried out by removal of the p-methoxy-
benzyl protecting group and oxidation of the primary al-
cohol to the corresponding acid, followed by Yamaguchi
moted anti-aldol reaction, the 1-(tosylamino)indan-2-ol
ester ent-37 and N,N-diisopropylethylamine were added
to a mixture of butanal (2 equiv), titanium tetrachloride (2
equiv), and acetonitrile (2 equiv) at –78 °C to give anti-al-
dol adduct 70 in 65% yield and excellent diastereoselec-
tivity (37:1 by H NMR and 13C NMR spectroscopy).
lactonization to provide macrolactone 69. This was then
converted into (+)-peluroside A.
1
Benzyl protection of aldol adduct 70 followed by lithium
aluminum hydride reduction and subsequent oxidation of
O
O
Me
the resulting alcohol gave aldehyde 71. The C2- and C3-
stereocenters were installed by using an Evans syn-aldol
procedure.1 The reaction between the chiral oxazolidi-
none 50 and aldehyde 71 in N,N-diisopropylethylamine
containing dibutylboryl triflate gave the aldol product 72
in 89% yield (7:1 dr). Aldol product 72 was protected as a
methoxymethyl ether, and the chiral auxiliary was re-
moved. The resulting acid was coupled with L-phenylala-
nine and then esterified with N-benzyloxycarbonyl-N-
methylphenylalanine. This provided the protected amino
ester 73. Interestingly, initial attempts at macrolactamiza-
tion resulted in complete epimerization at the C11 stereo-
center. Other coupling reagents, including O-(benzo-
triazol-1-yl)-N,N,N¢,N¢-tetramethyluronium tetrafluoro-
borate and (benzotriazole-1-yloxy)tris(dimethylami-
no)phosphonium hexafluorophosphate, gave the same
epimerized product. To overcome the steric constraints of
the 12-membered ring, our strategy was altered to gener-
ate the ketone at C3 and install the C2-methyl group after
macrolactamization.
O
N
BnO
ref. 43
OTES
H
66
65
Ph
Me
OBn
OTES
CHO
67
MeO
PMBO
OMe
Me
OBn
MOMO
OTES TBSO
L-Selectride
64
67, –78 °C, 1 h
O
HO
Ts
Ts
(92%)
NH
NH
O
OH
O
O
TiCl4, DIPEA
C3H7CHO
MeO
O
Me Me
68
O
O
Me
70
ent-37
O
O
N
O
O
H
O
OMe
OH
O
O
Me
OBn
Me
O
OBn
H
O
N
O
50
Ph
MOMO
TBSO
Me
H
DIPEA
Bu2BOTf
Me
HO
Bn
O
Ph
71
7
peloruside A (7)
72
O
MeO
O
O
O
Me Me
69
Me
NH
MOM
11
Scheme 10 Synthesis of intermediate 67 and completion of the syn-
thesis of peloruside A
O
O
Me
O
Me
O
NH
N
O
Me
Me
Ph
Stereocalpin A
O
O
OMe
N
Me
The antitumor depsipeptide stereocalpin A (8) was isolat-
ed from the dry lichen Ramalina terebrata in 2008.47 This
12-membered cycloamide shows good activity against
human colon, skin, and liver solid tumor cell lines. In ad-
dition, stereocalpin displays protein tyrosine phosphatase
O
Cbz
11-epi-stereocalpin A (74)
73
Ph
Scheme 11 Synthesis of 11-epi-stereocalpin A
Synthesis 2009, No. 17, 2992–3002 © Thieme Stuttgart · New York

PAPER
Asymmetric Aldol Reactions
2999
As shown in Scheme 12, aldehyde 75 was subjected to a Recently, through a structure-based approach, we have
Mukaiyama aldol protocol using ketene acetal 76 to give designed a series of exceedingly potent nonpeptidyl HIV
aldol product 77 in 72% yield (5:1 dr).2,49 Hydrolysis of PIs.52 One inhibitor, TMC114 (79; Daranuvir) has been
methyl ester 77 followed by ethyl-N¢-(3-dimethylamino- approved by the FDA for the treatment of drug-resistant
propyl)carbodiimide-mediated coupling with L-phenyl- HIV.53 A key feature of these potent inhibitors is the in-
alanine and subsequent oxidation gave the desired keto corporation of a stereochemically defined bis-THF as the
amide. Benzyl deprotection and esterification with N-ben- P2-ligand. This ligand was designed to maintain backbone
zyloxycarbonyl-N-methyl-L-phenylalanine gave ester 78. hydrogen-bonding interactions at the active site of the
This was converted into the corresponding cycloamide in protease. Another inhibitor, GW0385 (80, Brecanavir),
47% yield, along with 10% of the epimerized product. which also contains the bis-THF ligand, has undergone
Methylation from the less-hindered face using cesium car- phase II clinical trials.54
bonate and methyl iodide completed the synthesis of the
compound with the proposed structure of stereocalpin A;
however, our spectral data for the synthetic stereocalpin
did not match those for natural stereocalpin, which led us
to believe that the absolute stereochemistry of stereo-
calpin had been assigned incorrectly.47
NH2
OH
H
H
N
O
H
N
S
O
O
O
O
H
Ph
O
79 (TMC-114 or Darunavir)
OH
O
H
OBn
BF3⋅OEt2
Me
OMe
O
TBSO
O
O
Me
77
OH
O
H
H
N
75
MeO
O
H
N
S
76
Bn
O
O
O
O
H
O
O
O
O
O
O
O
N
S
Me
O
NH
Me
Me
NH
Me
80 (GW0385 or Brecanavir)
O
O
N
O
Me
Figure 2 Structure of protease inhibitors 79 and 80
OMe Ph
Me
N
O
Cbz
stereocalpin A (8)
We have developed a number of synthetic routes for pre-
paring the key bistetrahydrofuran ligand in an optically
active form. Our previous method using diethyl (3R)-
malate as a key starting material was overall not very ef-
ficient. We subsequently developed a procedure that re-
quired a lipase-catalyzed enzymatic resolution; this,
however, resulted in optical purity in the range 92–96%
ee.55 Synthesis of the ligand by means of a diastereoselec-
tive Michael addition reaction has been recently reported
by Quaedflieg and co-workers.56 To obtain the bistetrahy-
drofuran ligand efficiently and in high optical purity, we
carried out a synthesis using a titanium-enolate based
anti-aldol reaction as the key step.6
78
(proposed structure)
Ph
Scheme 12 Synthesis of the compound with the proposed structure
of stereocalpin A
(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol Ligand
The development and FDA approval of the first protease
inhibitors (PIs) in 1996 marked a new era of HIV/AIDS
management. HAART (highly active antiretroviral thera-
py) drug combinations containing PIs arrested the pro-
gression of HIV/AIDS by reducing the viral load and
increasing the CD4+ lymphocyte cell count in HIV/AIDS
patients.50 Gaining the upper hand in the battle against
HIV/AIDS proved bittersweet, as it became apparent that
these potent first-generation PIs had several drawbacks,
including high toxicity and related side-effects, high ther-
apeutic doses, and expensive treatment costs. The emer-
gence of multi-drug-resistant HIV-1 variants also became
a major problem. Drug-resistant HIV is responsible for
nearly 40–50% of patients who have previously shown
viral suppression to undetectable levels, to rapidly experi-
ence treatment failure.51 In addition, resistant HIV-1
strains have probably been transmitted, as 20–40% of pre-
viously untreated HIV-infected individuals have shown
continued viral replication despite HAART treatment
regimens.
As shown in Scheme 13, aldol condensation product 81
was obtained in 70% yield and a 96:4 anti/syn ratio by the
reaction of ester 29 with cinnamaldehyde. Subsequent
manipulations of the aldolate, including protection, reduc-
tion, Swern oxidation of the alcohol, and protection of the
resulting aldehyde gave the methyl acetal 82. Ozonolysis
of 82, followed by reduction of the resulting aldehydes,
gave the corresponding diol. This diol was treated with
aqueous hydrochloric acid, which resulted in deprotection
and acid-catalyzed cyclization to provide the desired
ligand 83 with a very high optical purity (>99% ee Mosher
ester analysis).
Synthesis 2009, No. 17, 2992–3002 © Thieme Stuttgart · New York

3000
A. K. Ghosh, Z. L. Dawson
PAPER
Example of a Titanium Enolate syn-Aldol Reaction: (1S,2R)-1-
(Tosylamino)indan-2-yl (2S,3R)-4-(Benzyloxy)-3-hydroxy-2-
methylbutanoate (44)
Ts
Ts
NH
NH
O
OH
O
TiCl4
DIPEA
O
O
Neat TiCl4 (1.47 mL, 13.4 mmol) and DIPEA (7.75 mL, 44.5 mmol)
were added to a soln of propionate ent-37 (4.0 g, 11.1 mmol) in
CH2Cl2 (150 mL) at 0 °C. The resulting soln was warmed to 23 °C,
stirred for 2 h, and then cooled to –78 °C. A mixture of TiCl4 (3.68
mL, 33.4 mmol) and BzOCH2CHO (3.13 mL, 22.3 mmol) in
CH2Cl2 (20 mL) was slowly added, and the dark soln was stirred for
2 h at –78 °C. The reaction was quenched with sat. aq NH4Cl, and
the mixture was warmed to 23 °C. The aqueous layer was separated
and extracted with CH2Cl2. The combined organic layers were
washed with brine, dried (Na2SO4), and concentrated to give a
brown residue that was purified by column chromatography to pro-
vide the pure product; yield: 5.27 g (93%).
cinnamaldehyde
(70%)
Ph
81
29
H
1. ozonolysis
Me2S
then NaBH4
OH
H
MeO
MeO
OTHP
O
Ph
H
2. HCl (aq)
82
83
O
Scheme 13 Synthesis of a bistetrahydrofuran ligand
Examples of Titanium Enolate anti-Aldol Reaction: (1S,2R)-1-
(Tosylamino)indan-2-yl(1S,2R)-3-Hydroxy-2-methylhexanoate
(70)
TiCl4 (4.34 mL, 39.6 mmol, 1.1 equiv) was added dropwise to a soln
of propionate ent-37 (12.93 g, 36 mmol) in CH2Cl2 (180 mL) at 0
°C and the mixture was stirred at 0 °C for 15 min before DIPEA
In conclusion, the expansion of aldol methodologies has
contributed significantly to advancing the synthesis of
natural products. Our titanium enolate mediated syn- and
anti-aldol strategies have been a cornerstone of our syn-
theses of b-hydroxy a-alkyl carbonyl derivatives. We (23.8 mL, 137 mmol, 3.8 equiv) was added slowly. The dark soln
was allowed to warm to 23 °C and stirred at 23 °C for 2 h. In a sep-
have incorporated this strategy into an efficient synthesis
arate flask, TiCl4 (7.9 mL, 2 equiv) was added slowly to PrCHO (6.5
of an optically pure form of the bistetrahydrofuran ligand,
mL, 72 mmol, 2 equiv) in CH2Cl2 (180 mL) at –78 °C, followed by
which is a crucial component of potent HIV protease in-
hibitors. We have also used Evans aldol reactions in the
addition of anhyd MeCN (3.8 mL, 2 equiv). The mixture was stirred
at –78 °C for 5 min while a white precipitate formed. The soln of the
syntheses of a number of natural products. Furthermore,
titanium enolate prepared from ent-37 was added to this mixture
we have recently developed a novel L-Selectride-mediat-
ed reductive aldol reaction and have demonstrated its use-
fulness by synthesizing the anticancer natural product
peloruside A.
from a cannula, over 15 min. The resulting dark soln was stirred at
–78 °C for 2 h, and then the reaction was quenched with sat. aq
NH4Cl. The aqueous layer was extracted with CH2Cl2, and the com-
bined organic phases were washed with brine and dried (Na2SO4).
The solvent was removed under reduced pressure and the residue
was purified by column chromatography (silica gel, hexanes–
Natural products will continue to stimulate scientists in all
disciplines. These natural masterpieces have been, and EtOAc, 9:1); yield: 10.1 g (65%; 37:1 dr).
will continue to be, mirrored through the art of organic
(1S,2R)-1-(Tosylamino)indan-2-yl (3S,4E)-2-Allyl-3-hydroxy-5-
phenylpent-4-enoate (81)
synthesis. The struggles and achievements on the path to
the synthesis of bioactive natural products will continue to
enrich the ever-expanding tapestry of chemical methodol-
ogies.
A 1.8 M soln of TiCl4 (13.8 mL, 24.8 mmol) was added dropwise to
a stirred soln of pent-4-enoate 29 (7.89 g, 20.5 mmol) in CH2Cl2
(210 mL) at 0 °C under an inert atmosphere. The resulting soln was
stirred for 5 min and then DIPEA (13.9 mL, 79.7 mmol) was added
dropwise. The mixture was allowed to warm to 23 °C and stirred for
2 h. In a separate flask, a 1.8 M soln of TiCl4 in CH2Cl2 (11.5 mL,
20.7 mmol) was added dropwise to cinnamaldehyde (5.30 mL, 42
mmol) in CH2Cl2 (320 mL) at –78 °C, and the soln was stirred for 5
min at –78 °C. DIPEA (7.3 mL, 41.9 mmol) was then added drop-
wise and the resulting mixture was stirred for an additional 5 min.
The titanium enolate soln prepared from pent-4-enoate 29 was add-
ed dropwise through an insulated cannula over 30 min, and the mix-
ture was stirred at –78 °C for 3.5 h. The reaction was quenched with
sat. aq NH4Cl and the mixture was allowed to warm to 23 °C. The
layers were separated and the aqueous layer was extracted with
CH2Cl2. The combined organic layers were washed with brine,
dried (Na2SO4), and concentrated to give a crude aldol product that
was purified by chromatography (silica gel, 15% then 20% EtOAc–
hexanes) to give diastereomerically pure anti-aldol product 81 as a
gummy solid; yield: 7.43 g (70%).
Example of an Evans syn-Aldol Reaction: (4R)-4-Benzyl-3-
[(2R,3S,4R,5S)-5-(benzyloxy)-3-hydroxy-2,4-dimethyloc-
tanoyl]-1,3-oxazolidin-2-one (72)
A 1 M soln of Bu2BOTf in CH2Cl2 (8.5 mL, 8.5 mmol) and DIPEA
(1.6 mL, 9.3 mmol) were added sequentially to a soln of (4R)-4-ben-
zyl-3-propionyl-1,3-oxazolidin-2-one (50; 1.81 g, 7.74 mmol) in
CH2Cl2 (30 mL), and the clear soln was stirred at 0 °C for 30 min
then cooled to –78 °C. A soln of aldehyde 71 (1.32 g, 5.96 mmol)
in CH2Cl2 (10 mL) was then slowly added by syringe. The aldehyde
flask was washed with CH2Cl2 (5 mL) and the remaining soln was
also added to the enolate soln. The mixture was stirred at –78 °C for
10 min then warmed to 0 °C over 1 h. The reaction was quenched
with pH 7 buffer (10 mL) and MeOH (15 mL). A 30% soln of H2O2
(10 mL) and MeOH (20 mL) were slowly added while the internal
temperature was kept below 5 °C. The mixture was stirred at 0 °C
for an additional 1 h then diluted with CH2Cl2 (40 mL). The aqueous
layer was extracted with CH2Cl2 and the combined extracts were
washed with brine, dried (Na2SO4), and concentrated under vacu-
um. The crude product was purified by flash column chromatogra-
phy (silica gel, hexanes–EtOAc, 85:15); yield: 2.45 g (89%).
Example of an L-Selectride-Mediated Reductive Aldol Reac-
tion: Aldol Product 68
A 1.0 M soln of L-Selectride in THF (1.1 mL, 1.1 mmol) was added
to a soln of enone 64 (645 mg, 1.06 mmol) in Et2O (200 mL) at
–78 °C, and the mixture was kept at –78 °C for 10–15 min. A soln
of aldehyde 67 (520 mg, 1.2 mmol) in Et2O (20 mL) was added at
–78 °C, and the mixture was stirred at –78 °C for 1 h. The reaction
Synthesis 2009, No. 17, 2992–3002 © Thieme Stuttgart · New York

PAPER
Asymmetric Aldol Reactions
3001
was quenched with sat. aq NH4Cl, and the organic layer was sepa-
rated. The aqueous layer was extracted with EtOAc, and the com-
bined organic layers were washed with H2O and brine then dried
(Na2SO4) and concentrated in vacuo. The crude product was puri-
fied by column chromatography to give the major isomer 68; yield:
823 mg (92%; dr 4:1).
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