A Total Synthesis of Salinosporamide A

Article abstract of DOI:10.1002/chem.201800046

Salinosporamide A is a β-lactone proteasome inhibitor currently in clinical trials for the treatment of multiple-myeloma. Herein we report a short synthesis of this small, highly functionalized, biologically important natural product that uses an oxidative radical cyclization as a key step and allows for the preparation of gram quantities of advanced synthetic intermediates.

Full text of DOI:10.1002/chem.201800046

A Journal of
Accepted Article
Title: A Total Synthesis of Salinosporamide A
Authors: Jonathan William Burton and Léo Boris Marx
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10.1002/chem.201800046
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A Total Synthesis of Salinosporamide A
Léo B. Marx,[a] and Jonathan W. Burton*[a]
Abstract: Salinosporamide A is a b-lactone proteasome inhibitor
currently in clinical trials for the treatment of multiple-myeloma.
Herein we report a short synthesis of this small, highly functionalized,
biologically important natural product that uses an oxidative radical
cyclization as a key step and allows the preparation of gram quantities
of advanced synthetic intermediates.
product in enantiopure form.[6-9] It is surprising, given all of the
advances in synthetic methodology over the previous decades,
that only three of the reported total syntheses of salinosporamide
A (1) have fewer than 20 steps and a number have greater than
30 steps. These step counts, subjective as they may be,
demonstrate the synthetic challenge that such
a densely
functionalized, stereochemically rich molecule presents. Herein
we report a novel 16 step (9 chromatographed intermediates)
stereocontrolled synthesis of salinosporamide A (1) that features
an oxidative radical cyclization and a selenolactonization as key
steps and provides gram quantities of key synthetic intermediates.
Introduction
In 2003, Fenical and co-workers reported the isolation, structure
determination and cancer cell cytotoxicity of the marine-derived
2]
natural product salinosporamide
A
1
(Figure 1).[1,
Results and Discussion
Salinosporamide A, is structurally closely related to omuralide 2,
the ring-closed form of lactacystin 3, in that they both contain a
pyrrolidinone fused to a b-lactone which is key to their biological
activity. Both 1 and 2 are small molecule proteasome inhibitors
whose mechanism of action involves esterification of an N-
terminal threonine residue of the 20S proteasome by the
electrophilic β-lactone.[3] Given the higher proteasome activity
exhibited by cancer cells, proteasome inhibition is an active area
of research for cancer chemotherapy. Indeed, salinosporamide A
has entered clinical trials for the treatment of multiple-myeloma,
solid tumors or lymphoma.[4, 5]
Retrosynthetic Analysis
Our retrosynthetic analysis of salinosporamide A (1) is delineated
in Scheme 1. In the first synthesis of salinosporamide A,6a Corey
reported an elegant method to install the C-5 and C-6
stereocenters of 1 that involved addition of a cyclohexenylzinc
reagent to a [4.3.0]-bicyclic aldehyde. Variations of this method
have been used by the majority of researchers to set the C-5 and
C-6 stereocenters of 1 and we elected to investigate this method
for our synthesis.
We therefore decided to synthesize
salinosporamide A (1) from the lactone-lactam 4 which would, in
turn, be made from the fused bicyclic aldehyde 5 on addition of
the appropriate cyclohexenyl organometallic. Taking our cue
from Danishefsky’s synthesis of salinosporamide A6c (the second
synthesis of the natural product), we reasoned that the C-3 tertiary
H
Me
Me
Me
H
N
Me
H
N
6
H
N
O
O
O
5
OH
O
OH
OH
1
4
alkoxy-bearing
stereocenter
could
be
installed
by
2
O
3
NHAc
CO2H
S
Me
Me
selenolactonization onto the 1,1-disubsituted alkene contained
within 6. The alkene 6 would itself be prepared from the selenide
7 with the selenide being formed by nucleophilic opening of the
[3.3.0]-bicyclic γ-lactone 8. A key step in our synthesis of
salinosporamide A was to be the oxidative radical cyclization of
the amidomalonate 9 to give 8. We have recently shown that N-
PMB-protected amidomalonates bearing pendent alkenes form
[3.3.0]-bicyclic γ-lactones under oxidative radical conditions and
used this methodology in our formal synthesis of 1.8g All of the
previous syntheses of salinosporamide A (1) have, at some point
involved, protection of the lactam NH (frequently as an N-PMB
group)[6-9] and it appeared that such lactam protection was crucial
to the successful synthesis of salinosporamide A (1); our first
target was therefore the tertiary amide 9a (with the choice of ester
to be determined by experiment). In the event, we found that the
secondary amide 9b (R = Me or tBu, R’ = H) was a competent
substrate for oxidative radical cyclization to form the [3.3.0]-
bicyclic γ-lactone 8b (R = Me or tBu, R’ = H) and we carried the
unprotected amide/lactam through the complete synthetic
sequence to the natural product itself (vide infra).
O
O
O
Me
H
HO
Cl
salinosporamide A; 1
lactacystin; 3
omuralide; 2
Figure 1. Salinosporamide A, omuralide and lactacystin.
This biologically important natural product presents a significant
challenge to synthetic chemists as it contains a high concentration
of both electrophilic and nucleophilic functional groups within a
small [3.2.0]-bicyclic core containing five contiguous
stereocenters including adjacent quaternary centers.
The
biological activity exhibited by 1 coupled with its interesting
structure has resulted in nine total syntheses of the natural
[a]
Dr L. B. Marx, Dr J. W. Burton
Department of Chemistry, University of Oxford, Chemistry Research
Laboratory, Mansfield Road, Oxford OX1 3TA UK
E-mail: jonathan.burton@chem.ox.ac.uk
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201800046
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withdrawing malonate functionality. Coupling of deactivated
amines such as 16 would require a highly electrophilic activated
carboxylic acid component; however, activation of β-carboxy
carboxylic acids (such as 14) can result in the formation of the
corresponding anhydrides (e.g. 17).[12, 13] Both the formation of
17 coupled with the low nucleophilicity of 16 results in the
formation of 15 being highly challenging. Acid fluorides have
been reported to prevent anhydride formation allowing coupling of
β-carboxy carboxylic acids substrates,[13] however, the
corresponding acid fluoride derived from 14 (νmax = 1836 cm-1)
failed to undergo amide bond formation with 16 (or derivatives).
Indeed, under a wide variety of amide bond forming conditions we
failed to form any of the desired product 15.[14] We reasoned that
reducing the steric bulk of the amine partner might result in
successful amide bond formation. We therefore investigated
amide formation between dimethyl aminomalonate 18, with
reduced steric hindrance both at nitrogen and at the malonate
esters. In the event amide coupling was readily achieved between
the acid 14 and dimethyl aminomalonate 18 in the presence of
HATU (Scheme 3). Oxidative elimination of the phenylselanyl
group from 19 occurred in good yield using a modification of the
procedure reported by Kocienski[15] to give cyclization substrate
H
H
O
R'
N
R'
N
H
O
O
O
N
OH
CO2R
OH
O
H
H
CO2R
Me
Me
O
Me
O
O
Cl
1
4
5
O
O
OH
R'
N
R'
N
R'
N
O
O
O
CO2R
O
CO2H
CO2R
CO2R
O
H
SePh
tBuO2C
CO2tBu
tBuO2C
8a; R' = PMB
8b; R' = H
7
6
O
CO2R
O
CO2R
CO2R
+
N
CO2R
OH
CO2R
R'
R'HN
CO2tBu
10
9a; R' = PMB
9b; R’ = H
11a; R' = PMB
11b; R' = H
Scheme 1. Retrosynthetic analysis of salinosporamide A (1).
20.
We have previously shown that N-PMB protected
Synthesis
amidomalonates bearing terminal alkenes readily undergo
cyclization to form the corresponding [3.3.0]-bicyclic γ-lactones
and had found that cyclization of simple N-unprotected
amidomalonates bearing terminal alkenes was capricious.8g
We initially prepared the carboxylic acid 14 in 73% yield by
alkylation of the known oxazolidinone 128g using t-butyl
bromoacetate followed by hydrolysis (Scheme 2).[10] We aimed
to convert 14 into the amidomalonate 15 by coupling of the acid
chloride derived from 14 with the readily prepared aminomalonate
16 (ESI) under Shotten-Baumann conditions.[6e],[11] Thus,
exposure of the acid 14 to oxalyl chloride followed by addition of
the amine 168g resulted in quantitative recovery of 16 after workup
and formation of the corresponding dicarboxylic acid derived from
14 (mass spectrometry evidence).
O
O
CO2Me
N CO2Me
a) dimethyl aminomalonate 18,
HATU
PhSe
PhSe
OH
84%
H
tBuO2C
tBuO2C
14
19
b) NaIO4, then heat
79%
CO2Me
O
O
O
O
O
CO2Me
CO2Me
a) NaHMDS,
BrCH2CO2tBu
PhSe
PhSe
H2N
CO2Me
18
N
O
N
O
N
H
85%
tBuO2C
Bn
Bn
tBuO2C
12
13
20
O
Scheme 3. Synthesis of amide 20. Reagents and conditions: a) dimethyl
aminomalonte 18, HATU, i-Pr2NEt, DMF, 0 °C to RT, 84%; b) NaIO4, NaHCO3,
MeOH, THF, water, then heat in toluene, 79%.
CO2Bn
O
b) BnOLi, then LiOH
85%
PMBHN
CO2Bn
16
PhSe
O
17
O
CO2Bn
O
see text
PhSe
PhSe
Given these previous results we were delighted to find that
exposure of amidomalonate 20 to our standard conditions for
oxidative radical cyclization[16] resulted in the formation of the
desired [3.3.0]-bicyclic γ-lactone 23a in 48% yield along with the
uncyclized but oxidized products 21 and 22 (Scheme 4). 1H NMR
analysis of the crude reaction mixture indicated the [3.3.0]-bicyclic
γ-lactone 23a was formed as an 8:1 mixture along with what was
assumed to be diastereomer 23b (based on previous
experience).8g
N
PMB
CO2Bn
OH
tBuO2C
tBuO2C
15
14
Scheme 2. Synthesis of acid 14. Reagents and conditions: a) NaHMDS, THF,
-78 °C, 10 min, then BrCH2CO2tBu, -78 °C, 45 min, 85%; b) BnOH, nBuLi, THF,
0 °C, 45 min, add 13, -78 to 0 °C, then LiOH, MeOH, water, THF, 0 °C to RT,
16 h, 85%.
The failure of this seemingly simple amide bond forming reaction
is most likely attributable to the amine 16 being both sterically
encumbered, and of reduced nucleophilicity due to the electron
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minimise
A1,3-strain
H
O
O
E
E
O
O
H
H
E
[O] and
hydrolysis
N
CO2Me
O
E
E
•
H
H
•
O
O
[O]
N
H
E
E
N
CO2tBu
HN
CO2tBu
25b; s-trans
O
R
R
•
H
HN
HN
•
O
H
tBuO2C
E
H
H
E
tBuO2C
E
H
26; R = CH2CO2tBu
H
[O]
20; E = CO2Me
27; R = CH2CO2tBu
23a
25a; s-cis
H
N
E
O
CO2Me
O
CO2Me
CO2Me
OH
O
CO2Me
O
AcO or water
or
E
N
H
CO2tBu
N
H
CO2Me
OAc
N
H
tBuO2C
O
H
H
H
tBuO2C
tBuO2C
28
22
21
H
23a
= nOe
Scheme 5. Plausible mechanism for formation of products 21, 22 and 23a under oxidative radical conditions and 1H NMR nOes for compound 23a.
The configuration of the major diastereomer 23a was assigned by
1H NMR nOe experiments (Scheme 5). The formation of the
products 21, 22 and 23, most likely arises by oxidation of the
substrate 20 with MnIII to generate the captodative C-centered
radical 25 (Scheme 5).[17, 18] In order for 5-exo-trig cyclization to
occur from 25 it is necessary for this radical to adopt an s-trans
conformation 25b. Secondary amides are well known to adopt an
s-cis geometry preferentially and it is likely that the corresponding
radical s-cis 25a will also be the lower energy conformation
compared with s-trans 25b. The s-trans radical 25b can undergo
5-exo-trig cyclization from the pre-transition state assembly 26
with the carboxymethylene side chain occupying a pseudo-
equatorial position in the chair-like transition state.[19] The adduct
radical 27 then undergoes oxidation and lactonization to give the
product [3.3.0]-bicyclic γ-lactone 23a. Alternatively, competitive
oxidation of the captodative radical 25 to the corresponding
iminium ion (or imine) 28 may occur followed by trapping with
acetate anion or water giving 21 and 22.[20] The stability of the
“tetrahedral intermediates” 21 and 22 is undoubtedly a result of
them being the formal addition products to the tricarbonyl
compound dimethyl ketomalonate.[21]
The next step in the synthetic pathway required differentiation of
the γ-lactone carbonyl group from the remaining carbonyl groups
in 23a. Our synthetic strategy was to open the γ-lactone with the
highly nucleophilic phenylselanyl anion. Unsurprisingly exposure
of the [3.3.0]-γ-lactone 23a to the anion formed on reduction of
diphenyl diselenide with sodium borohydride,[22] resulted in
substitution at the methyl ester to give the lactone acid 24
(Scheme 4);[23] clearly a more sterically demanding ester group
was required.
Synthesis – Second Generation
The synthesis of the cyclization substrate 20, and successful
cyclization to give the bicyclic γ-lactones 23 had demonstrated the
feasibility of oxidative radical methodology to form [3.3.0]-bicyclic
γ-lactones
from
terminal
alkene-containing
secondary
amidomalonates. However, it was clear that a change of
malonate ester was required and we elected to use a di-tert-butyl
malonate as Danishefsky had demonstrated that tert-butyl esters
were compatible with lactone opening by the phenylselanyl
anion.[6c],[23] Additionally, we sought a shorter synthesis of the
acid coupling partner 10. As shown in the retrosynthetic analysis
(Scheme 1) we intended to synthesize the cyclization substrates
by direct amide bond formation between the enantiopure β,γ-
unsaturated acid 10 and aminomalonates represented by 11b.
We were fully aware that this might be a challenging amide bond
formation due to the reduced nucleophilicity of the amine 11b and
the distinct possibility of epimerization of the stereocenter in 10
during amide bond formation. Our first task was to synthesize the
acid, represented by 10, in enantiopure form.
O
E
O
E
O
E
a) Mn(OAc)3,
Cu(OTf)2
N
H
E
N
H
E
N
E
+
H
OAc
OH
tBuO2C
tBuO2C
tBuO2C
20; E = CO2Me
21
22
+
H
N
H
N
H
N
O
O
O
CO2H
O
CO2Me
O
CO2Me
O
b) PhSeNa
+
4
O
O
O
Oppolzer has reported that treatment of the enolate derived from
the β,γ-unsaturated sultam 29 (Scheme 6) with benzyl bromide
gave the corresponding α-benzylated product in good yield
(80%)[24] and excellent diastereoselectivity. Additionally, the
deconjugative methylation of the enolate derived from the sultam
31 has been reported by Golec.[25] Following these precedents,
treatment of the crotonyl substituted sultam 31 with LiHMDS
followed by the addition of tert-butyl bromoacetate gave the
sultam 32 in 88% yield and >20:1 diastereomeric ratio as a white
crystalline solid. Hydrolysis using hydroperoxide anion[26] gave
the desired carboxylic acid 33. The auxiliary 30 was separated
H
H
H
tBuO2C
tBuO2C
tBuO2C
24
23a
23b
Scheme 4. Initial cyclizations. Reagents and conditions: a) Mn(OAc)3, Cu(OTf)2,
MeCN, reflux; 23a, 48%; 23b, 5% (NMR yield); 21, 5-10% (NMR yield); 22, 5-
10% (NMR yield); b) (PhSe)2, NaBH4, DMF, 100 °C then add lactone 23a, 50 °C,
46%.
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from 33 by trituration with hexane giving the acid in 91% yield
(90% purity, 98.8% ee). The next challenge was to develop a
racemization free amide bond forming reaction between the chiral
non-racemic acid 33 and the amine 34. Initial trials using HATU
with either DIPEA or N-methylmorpholine as added base resulted
in the product 35 being isolated in 70-75% ee. Ringling recently
advocated the use of T3P (propylphosphonic anhydride) as a mild
reagent for racemization free amide bond formation.[27] Following
Ringling’s procedure, with a reaction temperature of 0 °C, gave
the amide 35 with 96% ee, while lowering the temperature
to -40 °C gave the desired product 35 in 65% yield (98.4% ee)
from the sultam 32. This short synthetic sequence allowed for the
preparation of multigram quantities of the cyclization substrate 35
with high yield and enantiomeric purity.
5). Although the influence of water was not profound, the best
yield of bicyclic lactone (±)-36 was found using a 50:3 ratio of
acetonitrile to water (entry 4). Pleasingly, these conditions were
transferable to gram scale with ready separation of the C-2
lactone diastereomers of 36 being achieved (entry 6). During
optimization of the cyclization the reaction was also conducted on
5 g of enantiopure material using a 9:1 ratio of acetonitrile:water
which gave the bicyclic lactone in 67% isolated yield (entry 7).
Although it is not immediately clear as to the reason for water
influencing the product distribution in the reaction of 35, we
postulate that the amount of water affects the oxidation potential
of the copper(II) salt which in turn could influence the product
distribution.
H
N
H
N
1Mn(OAc)3,
Cu(BF4)2•6H2O
tBuO2C
tBuO2C
O
O
O
CO2tBu
O
CO2tBu
CO2tBu
2
+
N
H
Me
Me
Me
Me
O
H
O
a) NaH then
crotonyl chloride
CO2tBu
tBuO2C
tBuO2C
(±)-35
(±)-36
(±)-37
NH
N
Me
82%
+
S
S
tBuO2C
O
O2
O2
30
31
tBuO2C
AcO
N
b) LiHMDS,
BrCH2CO2tBu
H
(±)-38
CO2tBu
88%
Table 1. Optimization of the cyclization of substrate (±)-35 with respect to
water content.
Me
Me
O
O
c) LiOH, H2O2
91%
HO
33
N
Entry[a]
MeCN/
(±)-36
crude %[b]
(±)-36
isolated %[c]
(±)-37
crude %[b]
(±)-38
crude %[b]
S
O2
CO2tBu
CO2tBu
32
water
tBuO2C
34
NH2
d)
1
50:0
50:1
50:2
50:3
50:5
50:3
50:5.5
89.5
93.2
95.2
94.8
93.1
n.d.[f]
n.d.[f]
65
10.5
4.7
0
tBuO2C
T3P, pyridine
Me
Me
65% (2 steps)
2
76
2.1
3.0
4.7
6.5
n.d.
n.d.
O
tBuO2C
tBuO2C
O
N
3
74
1.8
S
N
H
O2
29
4
78
1.5
35
CO2tBu
5
74
0.4
Scheme 6. Synthesis of amine 35. Reagents and conditions: a) NaH, toluene,
0 °C to RT then add crotonyl chloride, 0 °C to RT, 2 h, 82%; b) LiHMDS, THF,
HMPA, -78 °C, 30 min then BrCH2CO2tBu, THF -78 °C, 7 h, 88%; c) 30% H2O2,
LiOH, THF, water, 5 min, 91%; d) 34, T3P {[CH3CH2CH2OP(O)]3}, pyridine,
EtOAc, -40 to -10 °C, 6 h, 65% from 32.
6[d]
7[e]
80 (71)[g]
67[g]
n.d.
n.d.
[a] Mn(OAc)3•2H2O (3.0 equiv.), Cu(BF4)2•6H2O (0.3 equiv.), MeCN/H2O (see
column 2 for proportions), 105 °C (oil bath temperature), 30 min, 500 mg and
0.25 M in substrate. [b] mol% from crude 1H NMR spectrum. [c] Total isolated
yield of an 8.5-9.5:1 mixture of C-2 diastereomers (natural product numbering,
major diastereomer shown). [d] Reaction conducted on 4.06 g, 9.82 mmol of
material of 82% ee. [e] Reaction conducted on 5.93 g, 14.4 mmol of material of
>98% ee. [f] n.d. = not determined. [g] Yield of isolated pure single (2R)-
diastereomer (+)-36.
Cyclization Optimization
Having developed an efficient synthesis of the cyclization
substrate optimization of the oxidative radical cyclization was
required. Initial studies using racemic substrate (±)-35 with 2
equivalents of Mn(OAc)3 and 1 equivalent of Cu(OTf)2 in
acetonitrile at 80 °C gave the desired [3.3.0]-bicyclic γ-lactones
(±)-36 in 50-60% yield as a >8:1 mixture of C-2 diastereomers
along with the oxidized and uncyclized material (±)-38. Changing
the amount of CuII salt had little influence on the outcome of the
reaction. We moved to using cheaper Cu(BF4)2 and found that
the amount of water in the reaction mixture had an influence on
the product distribution of the reaction (Table 1). With no added
water in the reaction the desired lactones (±)-36 were formed as
a 9:1 mixture along with the methylene pyrrolidinone (±)-37 (Table
1, entry 1). Addition of water lead to increasing quantities of the
oxidized, but uncyclized malonate (±)-38 being formed (entries 2-
Optimization of the cyclization had given us access to gram
quantities of the enantiopure [3.3.0]-bicyclic γ-lactone (+)-36. The
next step in the synthesis involved opening of the g-lactone by
phenylselanyl anion. Attempted opening of the γ-lactone in (+)-
36 by exposure to phenylselanyl anion, formed by the reduction
of diphenyldiselenide with sodium borohydride, in DMF at 100 ºC
led to decomposition whereas no reaction was observed at 50 ºC.
Liotta showed that
a non-complexed, and hence more
nucleophilic anion is formed by reduction of diphenyl diselenide
by sodium metal, or deprotonation of benzeneselenol with sodium
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10.1002/chem.201800046
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hydride.[28] Pleasingly exposure of the enantioenriched γ-lactone
(+)-36 to phenylselanyl anion prepared by reduction of diphenyl
diselenide with sodium hydride[29] allowed reaction at room
temperature to give the fully substituted pyrrolidinone 39 after acid
base extraction (Scheme 7). Reduction of the carboxylic acid in
39 to the corresponding primary alcohol 40 proved problematic
with direct reduction using borane resulting in substrate
decomposition and attempted reduction of the corresponding
mixed anhydride with sodium borohydride resulting in numerous
uncharacterized products being formed.
HO
H
N
H
N
O
O
CO2tBu
a) PhSeBr, AgBF4
OH
H
CO2H
SePh
O
tBuO2C
O
42
41
b) PMBCl
84% from 41
HO
HO
H
H
N
O
H
O
N
H
CO2PMB
Me
CO2PMB
c) Bu3SnH
93%
O
O
SePh
H
H
O
O
O
O
N
CO2tBu
N
CO2tBu
CO2H
SePh
44
a) PhSeNa
43
O
O
H
Scheme 8. Synthesis of bicyclic lactone 44. Reagents and conditions: a)
PhSeBr, AgBF4, CH2Cl2, CH3CN, RT; b) 4-CH3O(C6H4)CH2Cl, K2CO3, DMF,
40 °C, 84% from 41; c) Bu3SnH, AIBN, toluene, 105 °C, 93%.
tBuO2C
tBuO2C
(+)-36
39
b) (COCl)2, DMF
then LiAlH(Ot-Bu)3
81%
[from (+)-36]
As part of optimizing the synthetic route we had prepared the tert-
butyl ester (±)-45 (inset Scheme 9) in racemic form and we used
this material to investigate the oxidation and cyclohexenylation
reaction following the excellent precedent from Corey.6a,b We
initially investigated the formation of the aldehyde derived from
oxidation of (±)-45. Using standard reagents such as the Dess-
Martin periodinane, pyridinium chlorochromate, or DMSO with
pyridineŸsulfur trioxide, followed by the usual aqueous workup,
either led to no reaction (PCC) or to decomposition. This was
surprising given that in a number of previous syntheses of
salinosporamide A (1), oxidation of related primary alcohols to the
corresponding aldehydes had been readily achieved using DMP;
however, in all of these cases, the pyrrolidinone nitrogen atom
was protected with either a benzyl-type protecting group or a
carbamate protecting group. Interestingly we found that 1H NMR
analysis of the oxidation of (±)-45 by DMP in d2-dichloromethane
showed clean conversion to the corresponding aldehyde (not
shown) in under one hour. Addition of water to the reaction
mixture followed by 1H NMR analysis showed clear
decomposition of the aldehyde, as did direct elution of the reaction
H
H
c) NaIO4,
then heat
O
O
N
CO2tBu
OH
N
CO2tBu
OH
quant.
SePh
tBuO2C
tBuO2C
41
40
Scheme 7. Synthesis of pyrrolidinone 41. Reagents and conditions: a) (PhSe)2,
NaH, THF, 65 °C, 90 min, then (+)-36, 18-crown-6, 0 °C then RT, 3 h; b) (COCl)2,
DMF, then LiAlH(OtBu)3, THF, MeCN, -78 °C to RT, 81% from (+)-36; c) NaIO4,
NaHCO3, THF, MeOH, water, RT, then CHCl3, reflux, quant.
Ultimately, we found that conversion of the acid 39 into the
corresponding acid chloride followed by reduction with lithium tri-
tert-butoxy aluminum hydride[30] gave the primary alcohol 40 in
81% yield from the bicyclic lactone (+)-36. Elimination of the
phenylselanyl group from 40 was achieved by oxidation and
thermal treatment to give the alkene 41 in quantitative yield. All
that remained for the synthesis of the fully functionalized
pyrrolidinone core of salinosporamide A 1 was installation of the
C-3 tertiary hydroxyl/alkoxy group.
1
mixture through silica or basic alumina. In a similar manner, H
The lactonization of the ester alkene 41 (for example to give 42
Scheme 8) was crucial to our synthetic strategy. After extensive
experimentation, we found that lactonization could be achieved
using the phenylselanyl cation as reported by Danishefsky for a
closely related selenocyclo-acetalization.6c Thus, exposure of the
alkene 41 to phenylselanyl bromide and silver(I) tetrafluoroborate
led to lactonization with concomitant loss of the tert-butyl ester to
give the γ-lactone 42 (νmax 1780 cm-1) in 90% yield (Scheme 8);
the free carboxylic acid was readily converted into the
corresponding PMB ester 43 and the phenylselanyl group was
reduced under radical conditions to give 44. Stereoselective
introduction of the cyclohexenyl side-chain, conversion of the γ-
lactone into the C-2 chloroethyl group and β-lactone formation
were now required to complete the synthesis of salinosporamide
A (1).
NMR analysis of the DMP oxidation of alcohol 44, in both d2-
dichloromethane and d8-THF demonstrated clean conversion to
the corresponding aldehyde (not shown).
We therefore
developed a one-pot oxidation, alkylation procedure. Treatment
of the alcohol 44 with 2 equivalents of DMP in THF at ambient
temperature followed by cooling of the reaction mixture to −78 °C
and addition of 10 equivalents of cyclohexenylzinc bromide 467c
gave the desired product 47 as a single diastereomer in 56% yield
from the alcohol 44 (Scheme 9). This reaction was conducted with
>900 mg of alcohol 44 giving >600 mg of the cyclohexenyl-
substituted product 47. Reduction of the γ-lactone in 47 to the
corresponding diol 48 in the presence of the lactam and PMB-
ester was the next challenge. Lam8b had shown that reduction of
the γ-lactone in the N-PMB protected, methyl ester analogue of
47, occurred in 60% yield on treatment with two equivalents of
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10.1002/chem.201800046
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Me
Me
Me
Me
Me
Me
tBuO2
C
34
d)
O
O
O
tBuO2C
tBuO2C N
O
b) LiHMDS,
BrCH2CO2tBu
c) LiOH,
H2O2
tBuO2C
T3P, pyridine
NH2
a) NaH then
crotonyl chloride
NH
N
Me
N
HO
H
82%
88%
65% (2 steps)
S
S
S
O2
30
O2
31
O2
CO2tBu
CO2tBu
CO2tBu
e) Mn(OAc)3,
Cu(BF4)2
71%
32
33
35
OH
H
N
H
N
H
H
H
O
H
O
O
O
O
CO2tBu
N
CO2tBu
N
CO2tBu
CO2H
SePh
N
CO2tBu
O
i) PhSeBr,
AgBF4
h) NaIO4,
then heat
g) (COCl)2, DMF
then LiAlH(Ot-Bu)3
OH
OH
CO2H
*
f) PhSeNa
O
H
O
quant.
81% (2 steps)
SePh
SePh
42
j) PMBCl
tBuO2C
tBuO2C
tBuO2C
tBuO2C
41
40
39; 4.87 g
prepared
(+)-36; 9:1 dr*
O
84% (2 steps)
H
H
H
H
l) DMP then
n) BCl3
o) BOPCl
p) Ph3PCl2
OH
HO
H
N
H
N
H
N
H
N
O
O
H
O
O
O
m) DIBAl-H,
then NaBH4
ZnBr
N
OH
CO2PMB
Me
OH
CO2PMB
Me
OH
k) Bu3SnH
93%
46
H
H
CO2PMB
CO2PMB
O
56%
69%
61% (3 steps)
Me
O
Me
O
O
O
OH
SePh
HO
Cl
44
O
O
O
47; 645 mg
prepared
43; 2.31 g
prepared
48; 140 mg
prepared
1; 30 mg
prepared
Scheme 10. Total synthesis of salinosporamide A 1. Reagents and conditions: a) NaH, toluene, RT then add crotonyl chloride, 0 °C to RT, 2 h, 82%; b) LiHMDS,
THF, HMPA, -78 °C, 30 min then BrCH2CO2tBu, THF -78 °C, 7 h, 88%; c) 30% H2O2, LiOH, THF, water, 10 min, 91%; d) 34, T3P {[CH3CH2CH2P(O)O]3}, pyridine,
EtOAc, -40 to -10 °C, 6 h, 65% from 32; e) Mn(OAc)3•2H2O (3.0 equiv.), Cu(BF4)2•6H2O (0.3 equiv.), MeCN, water, 71% (desired diastereomer); f) (PhSe)2, NaH,
THF, 65 °C, 90 min, then (+)-36, 18-crown-6, 0 °C then RT 3 h; g) (COCl)2, DMF, then LiAlH(OtBu)3, THF, MeCN, -78 °C to RT, 81% from (+)-36; h) NaIO4, NaHCO3,
THF, MeOH, water, RT, then CHCl3, reflux, quant; i) PhSeBr, AgBF4, CH2Cl2, CH3CN, RT; j) 4-CH3O(C6H4)CH2Cl, K2CO3, DMF, 40 °C, 84% from 41; k) Bu3SnH,
AIBN, toluene, 105 °C, 93%. l. Dess-Martin periodinane, THF, RT, then cyclohexenylzinc bromide 46, -78 °C, 56%; m) DIBAl-H, THF, -10 °C, then MeOH, then
NaBH4, MeOH/THF, RT, 69%; n) BCl3, CH2Cl2, 0 °C. o. bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl), CH2Cl2, pyridine, then further BOPCl, RT; p) Ph3PCl2,
CH3CN, pyridine, RT, 61% (3 steps).
sodium borohydride in methanol to give the corresponding triol.
Using Lam’s procedure on 47 gave incomplete reduction of the γ-
lactone and a number of other products were formed as
evidenced by TLC analysis.
We found that exposure of the γ-lactone to DIBAl-H led to rapid
reduction (<20 min) of the γ-lactone to corresponding lactol
(LRMS analysis), which on addition of methanol and excess
sodium borohydride gave the triol 48. The PMB ester in 48 was
readily removed by treatment with boron trichloride and the total
synthesis was completed using the method of Corey,6a namely β-
lactone formation using BOPCl and chlorination with
triphenylphosphine dichloride to give salinosporamide A (1). The
analytical data for our synthetic salinosporamide A were in
excellent agreement for that of both the natural and previously
synthesized material.
H
a) DMP then
HO
H
N
H
N
O
O
ZnBr
OH
H
H
46
CO2PMB
Me
CO2PMB
Me
56%
O
O
HO
H
N
O
O
O
44
47
A summary of our synthesis is shown in Scheme 10. A number
of points are worthy of comment. The synthesis allows the
production of good quantities of key intermediates. We have
prepared gram quantities of the carboxylic acid 39 which were
transformed into gram quantities of the [3.3.0]-bicyclic γ-lactone
43. From intermediate 43 we have prepared 645 mg of the fully
elaborated pyrrolidinone 47. We ultimately synthesized 30 mg of
the natural product although our route would undoubtedly allow
us to prepare significantly more. The route proceeds in 16 steps
(5% yield) from the commercially available sultam 30 (15 steps
and 6% from commercially available sultam 31). For comparison,
Corey’s synthesis of 1 proceeds in 17 steps (9.8%) from threonine,
Fukuyama’s synthesis of 1 proceeds in 14 steps (19%) from 4-
pentenoic acid, and Romo’s bioinspired synthesis of 1 in 90% ee,
proceeds in 9 steps (3.6%) from serine. The key features of the
synthesis reported above include: the use of an oxidative radical
H
CO2tBu
Me
b) DIBAl-H, then NaBH4
69%
O
O
(±)-45
H
H
c) BCl3
H
N
H
N
d) BOPCl
e) Ph3PCl2
O
O
OH
O
OH
CO2PMB
61%
Me
O
Me
OH
Cl
HO
1
48
Scheme 9. Completion of the synthesis. Reagents and conditions: a) Dess-
Martin periodinane, THF, RT, then cyclohexenylzinc bromide 46, -78 °C, 56%;
b) DIBAl-H, THF, -10 °C, then MeOH, then NaBH4, MeOH/THF, RT, 69%; c)
BCl3, CH2Cl2, 0 °C; d) bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl),
CH2Cl2, pyridine, then further BOPCl, RT; e) Ph3PCl2, CH3CN, pyridine, RT,
61% (3 steps).
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10.1002/chem.201800046
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Fukuda, M. Tomizawa, T. Masaki, M. Shibuya, N. Kanoh, Y. Iwabuchi,
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(+)-36 with good diastereocontrol, a selenolactonization to set the
required C-3 tertiary-alkoxy stereocenter giving 42, and the use of
Corey’s method for diastereoselective introduction of the
cyclohexenyl side chain to give 47. Other notable aspects of our
synthesis include the scalability of the route and the limited use of
protecting groups as demonstrated by the unprotected
amide/lactam NH being carried through the whole synthetic
sequence.
[7]
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Conclusions
In conclusion, we have developed a short enantioselective
synthesis of the potent proteasome inhibitor salinosporamide A.
Work is ongoing to synthesize more complex, biologically active,
pyrrolidinone natural products using our oxidative radical
cyclization methodology.
[9]
Experimental Section
Supporting Information. Experimental procedures; spectroscopic and
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We thank the EPSRC for funding this work. The John Fell Oxford
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Léo B. Marx and Jonathan W. Burton*
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A Total Synthesis of Salinosporamide A
Herein we report a scalable total synthesis of the potent proteasome inhibitor
salinosporamide A that proceeds in 16 steps and 5% overall yield and features an
oxidative radical cyclization as a key step.
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