An enantioselective formal synthesis of (+)-lactacystin from hydroxymethyl glutamic acid (HMG)

Article abstract of DOI:10.1055/s-0029-1219207

A formal synthesis of (+)-lactacystin from hydroxymeth-ylglutamic acid (HMG), with an alkylidene carbene insertion reaction being used to construct the key nitrogen-bearing quaternary centre has been completed. Our route intercepts that of Shibasaki at an advanced pyrrolidinone intermediate, from which the synthesis can be completed following Donohoe's route. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0029-1219207

LETTER
535
An Enantioselective Formal Synthesis of (+)-Lactacystin from Hydroxymethyl
Glutamic Acid (HMG)
Enantioselective
F
b
ormal
S
ynth
d
a
u
ctacystin l Hameed, Alexander J. Blake, Christopher J. Hayes*
School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, UK
Fax +44(115)9513564; E-mail: chris.hayes@nottingham.ac.uk
Received 10 November 2009
Dedicated to Professor Gerald Pattenden in honour of his many outstanding contributions to organic chemistry
method6 revealed the lactam 2 (hereafter referred to as
Shibasaki’s intermediate) as an advanced precursor to 1.
The isopropyl group in 2 could be installed through a
Grignard addition to a suitably functionalized derivative
Abstract: A formal synthesis of (+)-lactacystin from hydroxymeth-
ylglutamic acid (HMG), with an alkylidene carbene insertion reac-
tion being used to construct the key nitrogen-bearing quaternary
centre has been completed. Our route intercepts that of Shibasaki at
an advanced pyrrolidinone intermediate, from which the synthesis of lactam 3, with the latter being derived from hydroxy-
can be completed following Donohoe’s route.
methyl glutamic acid (HMG; 4) through simple lactami-
sation.7
Key words: Lactacystin, hydroxymethyl glutamic acid, alkylidene
carbene, CH insertion
Although a number of alternative methods exist for the
enantioselective preparation of HMG,8 we chose to use
our previously developed synthesis, which utilizes an
The 26S proteasome inhibitor (+)-lactacystin (1)1,2 has be-
alkylidene carbene 1,5-CH insertion reaction to install
come a classic target for total synthesis and a large num-
ber of synthetic studies on this molecule have been
reported to date.3 In this Letter we describe our most re-
cent work on the synthesis of this biologically important
target, which has resulted in an enantioselective formal
synthesis of 1.
the key nitrogen-bearing quaternary stereocentre
(Scheme 2).9
Boc
Boc
N
a
N
O
O
O
OTBS
Ph3P
OTBS
O
8
Garner's aldehyde 6
O
Grignard
7
OH
Donohoe (C7-Me)
b
6
7
Shibasaki (C6-OH)
5
OH
OR
OH
O
O
N
N
Boc
S
NHAc
CO2H
H
H
Boc
N
O
O
2
c
O
N
H
(+)-lactacystin 1
OTBS
O
isopropyl
addition
O
OTBS
9
10
O
O
O
1,5-CH
insertion
lactamisation
OMe
HO
OH
O
N
O
O
H
H2N
Boc
HO
HO
N
HO
OH
HMG 4
3
d
BocN
O
OTBS
O
Scheme 1 Retrosynthetic analysis of lactacystin 1
11
12
Scheme 2 Reagents and conditions: (a) CH2Cl2, 7, r.t., 5 d, 83%; (b)
H2, Pd/C, EtOAc, 17 h, 86%; (c) TMSCHN2, THF, n-BuLi, –78 °C to
r.t., 90 min, 63–69%; (d) RuCl3, NaIO4, MeCN, H2O, CCl4, r.t., 88%.
Our retrosynthetic analysis of lactacystin (1) is shown in
Scheme 1. After disconnection of the N-acetyl cysteine
side-chain, we first chose to remove the methyl group at
C7. In our previous synthetic approach to 1, we experi-
enced difficulties installing this substituent with a high de-
gree of stereocontrol,4 so in our revised route we chose to
utilize Donohoe’s excellent method of late-stage enolate
alkylation5 for methyl group introduction. Further discon-
nection of the C6-hydroxy group using Shibasaki’s
The chemistry shown in Scheme 2 was performed on a
multi-gram scale and gave access to large quantities of the
protected HMG derivative 12 for use in the synthesis of 1.
Formation of lactam 3 was then achieved by formation of
the dimethyl ester 13,10 which was then deprotected using
sulfuric acid in methanol to afford a nearly equimolar
mixture of the ammonium salt 14 and the desired lactam
3 (Scheme 3). This mixture could easily be converted into
SYNLETT 2010, No. 4, pp 0535–0538
0
1.
0
3.
2
0
1
0
Advanced online publication: 19.01.2010
DOI: 10.1055/s-0029-1219207; Art ID: D32409ST
© Georg Thieme Verlag Stuttgart · New York

536
A. Hameed et al.
LETTER
essentially pure 3 in good yield (72%) by simply heating
the mixture at reflux in chloroform for 8–10 hours.
O
O
O
O
K2CO3, MeI
MeO
OMe
HO
OH
BocN
BocN
acetone, Δ
O
(70%)
O
12
13
H2SO4
MeOH
O
O
O
OMe
+
RO
OMe
O
N
H3N
14
H
OH
OH
3
CHCl3, 8–10 h
(72% overall)
Figure 1 X-ray crystal structure of aminal 19
Scheme 3
A variety of protecting group strategies (Boc, PMB and
TBS) were explored (data not shown) in order to over-
come this reactivity problem but, unfortunately, no ade-
quate solution could be found. We therefore returned our
attention to using the ester present in lactam 3 as the elec-
trophilic centre for isopropyl addition. Thus, N,O-ben-
zylidene aminal protection of 3 under standard conditions
afforded the desired product 19 as a single diastereoiso-
mer. The relative stereochemistry of 19 was confirmed
unambiguously by single crystal X-ray diffraction
(Figure 1).11 Direct addition of the isopropyl group to 19
using Kang’s method12 [i-PrMgBr (0.5 M in THF), THF,
–20 °C to r.t.] unfortunately failed (19→20; Scheme 4);
however, we were able to adopt a stepwise procedure that
ultimately led to the desired product (Scheme 5).
With significant quantities of 3 in hand, we could then ex-
amine installation of the isopropyl side-chain. Although
this particular batch of 3 was in the wrong enantiomeric
series, we decided to explore a very direct method for ac-
cessing ent-Shibasaki’s intermediate (16) by adding an or-
ganometallic reagent (i.e. Grignard reagent) to aldehyde
15. Unfortunately the aldehyde 15 proved to be difficult to
handle, and we could only produce trace amounts of the
desired product 16. We were confident that the problem
lay in the organometallic addition (15→16) rather than the
oxidation step (3→15), because a Wittig reaction on the
crude oxidation product 15, using the stabilized ylide 17,
afforded the expected product 18 in reasonable overall
yield (59%, 2 steps).
O
CO2Me
OMe
CO2Bn
O
N
H
O
N
H
HO
16
18
b
MgBr
CO2Bn
17
Ph3P
O
O
O
a
OMe
OMe
O
O
N
N
H
H
OH
O
3
15
c
MgBr
Figure 2 X-ray crystal structure of aminal 20
OH
OMe
O
N
O
N
O
O
Initial attempts to prepare aldehyde 22 directly from 19
were frustrated by the fact that the lactam carbonyl in 19
was preferentially reduced with DIBAL-H to afford the
hemiaminal 25 (and its ring-opened form 26, as judged by
1H NMR) in excellent yield. Sodium borohydride
(NaBH4, MeOH/THF), however, cleanly reduced the es-
ter to afford the desired alcohol 21 (93%), which was then
Ph
20
Ph
19
Scheme 4 Reagents and conditions: (a) DMP, CH2Cl2; (b)
Ph3PCH2CO2Bn, r.t., 3 d (59%, over 2 steps); (c) PhCH(OMe)2,
TsOH·H2O, toluene, reflux, 100%.
Synlett 2010, No. 4, 535–538 © Thieme Stuttgart · New York

LETTER
Enantioselective Formal Synthesis of (+)-Lactacystin
537
O
O
O
OMe
a, b
OH
OBn
HO
N
H
OMe
O
O
N
N
H
HN
O
O
O
HO
Ph
25
Ph
Ph
26
20
28
c–e
f
O
O
OH
f
OBn
CO2Et
OH
b
a
OMe
O
N
H
O
N
O
O
N
O
N
CO2Et
N
H
O
O
O
30
29
Ph
22
Ph
19
Ph
21
g
OH
c
Shibasaki
(ref. 6)
OH
O
O
N
S
NHAc
CO2H
O
N
H
CO2Et
H
O
OH
OH
31
(+)-lactacystin 1
O
O
e
d
N
N
O
O
Scheme 6 Reagents and conditions: (a) BnBr, TBAI, NaH (60% in
oil), THF, reflux, 15 h, 51% (+ recovered starting material); (b) pro-
panedithiol, CF3CH2OH+HCl (1.5% w/v), 16 h, 82%; (c) DMP,
CH2Cl2, 2 h; (d) NaClO2, NaH2PO4·2H2O, HSO3NH2, t-BuOH–H2O,
r.t., 16 h; (e) EtI, K2CO3, acetone, 30–40 °C, 61% (over 3 steps); (f)
Pd/C, H2, EtOH, 2 d, 88%; (g) DMP, CH2Cl2, 2 h, r.t., 74%.
Ph
20
Ph
24
(9:1)
MgBr
23
Scheme 5 Reagents and conditions: (a) NaBH4, MeOH–THF (1:1),
0 °C, 3 h, 93%; (b) DMP, CH2Cl2, 2 h, 75%; (c) i-PrMgBr (0.5 M in
THF), THF, –20 °C to r.t., 38% (21) / 35% (22); (d) 23 (0.5 M in
THF), THF, –78 °C, 5 h, 60% (+ recovered starting material); (e) Pd/
C, H2, EtOH, 2 d, 85%; (f) DIBAL-H, THF, –78 °C, 100%.
References and Notes
oxidized to 22 using Dess–Martin periodinane13 (75%).
Attempted addition of the isopropyl Grignard to 22 led
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group was added using Corey’s two-step sequence14 (iso-
propenyl Grignard addition followed by catalytic hydro-
genation), to afford 20 as the major new product. Single
crystal X-ray diffraction analysis confirmed the stereo-
chemistry at the newly formed carbinol stereocentre
(Figure 2).
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functional group manipulations. Thus, alcohol 20 was
protected as its benzyl ether and the aminal was deprotect-
ed under Moloney’s conditions.15 The resulting primary
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Synlett 2010, No. 4, 535–538 © Thieme Stuttgart · New York

538
A. Hameed et al.
LETTER
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Synlett 2010, No. 4, 535–538 © Thieme Stuttgart · New York