Synthetic studies of salinosporamide A through the intramolecular hydroamidation of alkynes

Article abstract of DOI:10.1016/j.jorganchem.2010.06.021

Rhodium-catalyzed intramolecular hydroamidation of alkynes was carried out to construct the synthetic intermediates of a proteasome inhibitor, salinosporamide A. Several alkynyl formamides were synthesized and subjected to the hydroamidation reaction. Som

Full text of DOI:10.1016/j.jorganchem.2010.06.021

Journal of Organometallic Chemistry 696 (2011) 42e45
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Synthetic studies of salinosporamide A through the intramolecular
hydroamidation of alkynes
,
Haruhi Kamisaki a, Yusuke Kobayashi b, Tetsutaro Kimachi b, Yoshizumi Yasui c, Yoshiji Takemoto a
*
a Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
b Faculty of Pharmaceutical Sciences, Mukogawa Women’s University, Nishinomiya, Hyogo 663-8179, Japan
c World Premier International Research Center, Advanced Institute for Materials Research, Tohoku University, Aoba, Sendai 980-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Rhodium-catalyzed intramolecular hydroamidation of alkynes was carried out to construct the synthetic
intermediates of a proteasome inhibitor, salinosporamide A. Several alkynyl formamides were synthe-
sized and subjected to the hydroamidation reaction. Some derivatives with a methoxymethyl (MOM) or
2-methoxy-2-propyl (MOP) group near the reaction site were converted to the corresponding lactams in
excellent yields.
Received 24 April 2010
Received in revised form
19 June 2010
Accepted 22 June 2010
Available online 30 June 2010
Ó 2010 Elsevier B.V. All rights reserved.
Keywords:
Rhodium carbonyl complexes
CeH activation
Alkynes
Hydroamidation
g-Lactams
1. Introduction
ring to yield g-lactam 2. This compound was envisioned to be
formed by a key intramolecular hydroamidation that requires
alkynyl formamide 3 as a precursor. Compound 3 could be obtained
by the alkynylation of keto amide 4. Oxidation of known amino
alcohol 5 [3a] derived from threonine will give ketone 4. Form-
amide 7, a cyclization precursor which lacks a methyl group at the
propargylic position, could be prepared via synthetic intermediates
8 and 9 by a sequence similar to that for 3 from serine. Comparison
of the hydroamidation of 7 with that of 3 may reveal the effect of
steric hindrance near the alkynyl group. Another substrate for
hydroamidation is acetal 11 which could be obtained from alde-
hyde 12. For the total synthesis, differentiation of the two diaster-
eotopic alkoxy groups in the acetal moiety of 10 is required after the
hydroamidation of 11. We were also interested in formamide 14
with a simple alkyl group instead of a siloxymethyl group on the
alkyne, since the bioactivities of salinosporamide A derivatives are
known to strongly rely on the substituent at this position [9].
The synthesis of salinosporamide A (1) [1], a potent and selec-
tive proteasome inhibitor, has attracted much interest due to its
important bioactivity and polysubstituted lactam structure [2ꢀ4].
In connection with our research on the synthesis of functionalized
lactams through transition-metal-catalyzed reactions [5], we have
launched a program directed toward the total synthesis of salino-
sporamide A. Our plan is based on the transition-metal-catalyzed
hydroamidation of alkynes. By applying this reaction intramolec-
ularly, we previously showed that a-alkylidene-g-lactams can be
synthesized from alkynyl formamides (Scheme 1) [6]. This
approach has advantages for the synthesis of functionalized lac-
tams in terms of ready access to cyclization precursors and neutral
reaction conditions. Preceding studies [7] on hydroamidation were
limited to simple substrates, and the reaction has rarely been
applied to natural product synthesis [8].
Our retrosynthetic analysis is shown in Scheme 2. To examine
the key intramolecular hydroamidation, four cyclization precursors
(3, 7, 11, and 14) were designed. The targeted salinosporamide A (1)
could be simplified by removing the cyclohexene moiety, opening
2. Results and discussion
the b-lactone, and introducing the exo-double bond in the lactam
The synthesis of 3 was attempted from amino alcohol 5 obtained
from threonine through oxazoline 15 [3a] (Scheme 3). Alcohol 5
was converted to keto formamide 4 by formylation and oxidation.
However, the alkynylation of 4 did not proceed despite numerous
* Corresponding author. Tel.: þ81 75 753 4528; fax: þ81 75 753 4569.
E-mail address: takemoto@pharm.kyoto-u.ac.jp (Y. Takemoto).
0022-328X/$ e see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2010.06.021

H. Kamisaki et al. / Journal of Organometallic Chemistry 696 (2011) 42e45
43
diastereomers, 7a (less polar) and 7a0 (polar). During this addition
process, the formation of retro-aldol product 17 was observed. This
causes a moderate yield of 7. Through appropriate protection of the
hydroxy group in 7a and 7a0, formamides 7bed and 7d0 were
obtained (7b: R2 ¼ Ac, 7c: R2 ¼ TES, 7d and 7d0: R2 ¼ MOP).
Formamides 11aed and 14a were synthesized in a straightfor-
ward manner (Scheme 5). Acetalization [11] of triol 18 followed by
benzylation gave amino alcohol 19. Selective N-formylation of this
amino alcohol was accomplished with ethyl formate and sodium
hydride in EtOH. Subsequent Swern oxidation gave aldehyde 12,
which was subjected to alkynylation with lithiated 3-siloxy-1-
propyne or 1-butyne. Quenching of the alkoxides in situ with
electrophiles such as water, TESCl, and MOMCl gave the corre-
sponding formamides 11aec and 14a. Compound 11d was
synthesized from 11a by the reaction with 2-methoxypropene.
R2
R2
H
Rh-catalyzed
hydroamidation
H
Functionalized lactams
O
N
R1
O
N
R1
Scheme 1.
and varied attempts; therefore, the cyclization precursor 3 was not
available.
On the other hand, the syntheses of 7aed, 7a0, and 7d0 were
feasible (Scheme 4). Similar to 4, aldehyde 8 was obtained in four
steps from serine via 16 [10] and 9. Addition of the lithium acetylide
gave the desired alkynyl formamide as
a
1:2 mixture of
R3
H
Cl
R1
R1
R2O
BnO
OTBS
R2O
R1
O
O
N
O
O
N
H
OTBS
O
BnO
MeO2C
CHO
BnO
MeO2C
CHO
+
N
N
XnM
HO
MeO2C
PMB
H
PMB
PMB
2 (R1=Me)
3 (R1=Me)
7 (R1=H)
4 (R1=Me)
8 (R1=H)
6 (R1=H)
(−)-salinosporamide A (1)
R3
H
R3
R1
OH
R1
MeO2C
OH
NH2
R3
R2O
R2O
O
BnO
MeO2C
XnM
+
O
NH
CHO
O
N
N
PMB
L-threonine
or
CHO
5 (R1=Me)
9 (R1=H)
PMB
O
PMB
O
L-serine
O
CHO
10 (R3=CH2OTBS)
13 (R3=Et)
11 (R3=CH2OTBS)
N
14 (R3=Et)
O
PMB
12
Scheme 2.
O
OH
OTBS
1) HCO2H
Ac2O
2) IBX
OH
O
N
XnM
3
BnO
MeO2C
CHO
Ar
BnO
MeO2C
X
N
NH
MeO2C
NH2
MeO2C
73%
PMB
4
PMB
15
Ar = 4-MeO-C6H4
5
L-threonine
Scheme 3.
H
O
N
OH
1) ArCOCl
1) LDA; BnOCH2Cl
HMPA, THF
1) HCO2H
Ac2O
OH
O
N
iPr2NEt
BnO
MeO2C
CHO
Ar
BnO
MeO2C
NH 2) IBX
PMB
2) SOCl2
2) NaBH3CN, AcOH
MeO2C
NH2
MeO2C
PMB
31%
70%
43%
L-serine
16
9
8
Ar = 4-MeO-C6H4
OTBS
OTBS
HO
R2O
BnO
MeO2C
BnO
OTBS
7b (R2= Ac)
Li
CHO
protection
CHO
BnO
MeO2C
CHO
N
7c (R2= TES)
7d (R2= MOP)
7d' (R2= MOP)
THF, −78 oC
60%
N
N
MeO2C
PMB
PMB
7a, 7a' (1:2)
PMB
17
Scheme 4.

44
H. Kamisaki et al. / Journal of Organometallic Chemistry 696 (2011) 42e45
OH
OH
CHO
N
1) Me2C(OMe)2
PPTS
1) HCO2Et, NaH
EtOH
O
CHO
HO
O
NH3Cl
NH
2) 4-MeO-C6H4CHO
then NaBH4
2) Swern
oxidation
O
PMB
HO
O
PMB
18
12
98%
19
15%
R3
R3
11a (R2= H, R3=CH2OTBS)
11b (R2= TES, R3=CH2OTBS)
11c (R2= MOM, R3=CH2OTBS)
14a (R2= MOM, R3=Et)
R2O
OMe
Li
11a
11d
cat. PPTS
54% (from 12)
THF, −78 oC
O
CHO
then R2-X
N
O
PMB
11d (R2= MOP, R3=CH2OTBS)
49−60%
Scheme 5.
Hydroamidation was performed with Rh4(CO)12 (20 mol%) in
xylene at 130 ꢁC (Table 1) [6]. When 7a with a free hydroxy group
was subjected to the reaction, -lactam 6a was obtained in 36%
5. The reaction was also insensitive to the configuration of the
starting materials 7d and 7d0. Similarly, hydroxy-free acetal 11a
gave lactam 10a in 30% yield (entry 7). The reaction of 11b
(R2 ¼ TES) was also unsatisfactory (entry 8). Although the MOP
group was cleaved during the reaction, compounds 11c and 11d
with either a MOM or MOP group were converted to the corre-
sponding lactams in acceptable yields (entries 9, 10). Since treat-
ment of MOM 14 bearing an ethyl group instead of a siloxymethyl
group under the same conditions furnished the desired product 13a
in a yield comparable to that of 11c (entry 11), the acetylene can
accommodate a simple alkyl group as an R3 substituent. The results
in Table 1 show that substrates with acetal moieties such as MOM
or MOP at the propargylic position gave better yields than others.
The origin of this effect is under investigation in our laboratories.
g
yield (entry 1). A significant amount of compound 17 (see Scheme
4) was also isolated (56%), which was probably formed by retro-
aldol fragmentation. The corresponding diastereomer 7a0 gave
similar results, which indicates that the stereochemistry at the
propargylic position does not affect the reaction (entry 2). The same
reaction of acetate 7b and silyl ether 7c did not give good results
(entries 3, 4). However, 2-methoxy-2-propyl (MOP) derivatives 7d
and 7d0 underwent hydroamidation to give lactams 6a and 6a0 in
high yields after unexpected cleavage of the MOP group (entries 5,
6). It is likely that the MOP group was cleaved after cyclization
because of the clear difference between the yields of entries 1 and
Table 1
Rhodium-catalyzed intramolecular hydroamidation of alkynyl formamides.a
OTBS
R3
R3
H
H
R2O
OTBS
R2O
R2O
R2O
Rh4(CO)12
O
or
O
O
CHO
O
BnO
MeO2C
N
or
BnO
MeO2C
CHO
N
xylene
130 °C
N
N
PMB
O
O
PMB
PMB
7a-d, 7a', and 7d'
PMB
11a-d and 14a
6a-c and 6a'
10a-c and 13a
Entry
Substrate
Product
Yield (%)b
c
1
2
3
4
5
6
7
7a (R2 ¼ H)
7a0 (R2 ¼ H)
7b (R2 ¼ Ac)
6a (R2 ¼ H)
6a0 (R2 ¼ H)
6b (R2 ¼ Ac)
6c (R2 ¼ TES)
6a (R2 ¼ H)
6a0 (R2 ¼ H)
10a (R2 ¼ H,
36
24
d
e
7c (R2 ¼ TES)
18 (53)
quant
92
7d (R2 ¼ MOP)
7d0 (R2 ¼ MOP)
11a (R2 ¼ H,
30
R3 ¼ CH2OTBS)
R3 ¼ CH2OTBS)
10b (R2 ¼ TES,
R3 ¼ CH2OTBS)
8
11b (R2 ¼ TES,
29 (22)
R3 ¼ CH2OTBS)
9
11c (R2 ¼ MOM, R3 ¼ CH2OTBS)
11d (R2 ¼ MOP,
R3 ¼ CH2OTBS)
10c (R2 ¼ MOM, R3 ¼ CH2OTBS)
10a (R2 ¼ H, R3 ¼ CH2OTBS)
61
48
10e
11
14a (R2 ¼ MOM, R3 ¼ Et)
13a (R2 ¼ MOM, R3 ¼ Et)
59
a
Reaction was carried out with Rh4(CO)12 (20 mol%) in xylene at 130 ꢁC for 2 h.
The values in parentheses show the yield of recovered starting materials.
Compound 17 (see Scheme 4) was isolated in 56% yield.
Compound 17 was isolated in 70% yield.
b
c
d
e
10 mol% of the catalyst was used.

H. Kamisaki et al. / Journal of Organometallic Chemistry 696 (2011) 42e45
45
In summary, we have developed concise synthetic routes to the
key intermediates of salinosporamide A and its analogs. Hydro-
amidation was shown to be feasible even for functionalized
substrates. It is worth noting that during the synthesis, the formyl
group which initially acted as a protecting group, was incorporated
into the molecular framework by its chemoselective activation with
the rhodium catalyst. The results described herein are a progressive
attempt to apply hydroamidation to total synthesis. Chemo-
selective activation of an inert functionality such as formamide
with a transition metal catalyst was shown to be an effective and
attractive synthetic strategy in a multistep synthesis. Further
investigations directed toward the total synthesis of salinospor-
amide A are currently ongoing in our laboratories.
3.53 (d, 1H, J ¼ 12.2 Hz), 3.41 (s, 3H), 3.07 (d, 1H, J ¼ 12.2 Hz), 2.40
(dq, 2H, J1 ¼14.7 Hz, J2 ¼ 7.4 Hz), 1.37 (s, 3H), 1.36 (s, 3H), 1.01 (t, 3H,
J ¼ 7.4 Hz); 13C NMR (126 MHz, CDCl3,
d) 168.4, 159.0, 143.0, 128.8,
114.0, 98.8, 93.6, 70.6, 62.7, 62.0, 60.2, 55.6, 55.2, 43.0, 26.4, 22.5,
20.5, 13.5; IR (ATR) 1685 cmꢀ1; HRMS (FABþ) C22H31NO6: (Mþ)
405.2151. Found 405.2149.
Acknowledgement
This work was supported in part by Grants-in-Aid for Scientific
Research B (No. 193990005) (Y.T.) and for Young Scientists B (No.
20790008) (Y.Y.), and “Targeted Proteins Research Program” from
the Ministry of Education, Culture, Sports, Science and Technology
of Japan.
3. Experimental
References
3.1. General procedure for rhodium-catalyzed intramolecular
hydroamidation
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3.1.1. Analytical data for lactam 6a
1H NMR (500 MHz, CDCl3,
d) 7.34e7.30 (m, 4H), 7.18e7.15 (m,
4H), 6.76 (d, 1H, J ¼ 8.6 Hz), 6.74 (ddd, 1H, J1 ¼ J2 ¼ 4.8 Hz,
J3 ¼ 2.1 Hz), 5.03 (dd, 1H, J1 ¼ 6.7 Hz, J2 ¼ 2.1 Hz), 4.62 (d, 1H,
J ¼ 15.3 Hz), 4.54 (dd, 1H, J1 ¼ 4.8 Hz, J2 ¼ 1.5 Hz), 4.53 (dd, 1H,
J1 ¼ 4.8 Hz, J2 ¼ 1.5 Hz), 4.47 (d, 1H, J ¼ 15.3 Hz), 4.27 (d, 1H,
J ¼ 11.9 Hz), 4.21 (d,1H, J ¼ 11.9 Hz), 3.87 (d,1H, J ¼ 10.4 Hz), 3.85 (d,
1H, J ¼ 10.4 Hz), 3.76 (s, 3H), 3.54 (s, 3H), 3.45 (d, 1H, J ¼ 6.7 Hz),
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ꢀ
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2983e2991;
0.91 (s, 9H), 0.11 (s, 6H); 13C NMR (126 MHz, CDCl3,
d) 171.1, 167.8,
158.8, 137.3, 136.5, 133.1, 129.6, 128.6, 128.5, 127.9, 127.6, 113.6, 73.3,
70.6, 67.8, 61.2, 55.2, 52.6, 44.7, 29.6, 25.8, ꢀ0.1, ꢀ5.5; IR (ATR) 3343,
1673 cmꢀ1; HRMS (FABþ) C30H41NO7Si: (Mþ) 555.2652. Found
555.2657.
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2711e2713;
3.1.2. Analytical data for lactam 6a0
1H NMR (500 MHz, CDCl3,
d) 7.34e7.31 (m, 3H), 7.21 (d, 2H,
J ¼ 7.0 Hz), 7.16 (d, 1H, J ¼ 8.6 Hz), 6.74 (d, 2H, J ¼ 8.6 Hz), 6.64 (dd,
1H, J1 ¼ 6.4 Hz, J2 ¼ 3.1 Hz), 5.11 (m, 1H), 4.63e4.52 (m, 3H),
4.39e4.30 (m, 3H), 3.90 (d, 1H, J ¼ 10.7 Hz), 3.82 (d, 1H, J ¼ 10.7 Hz),
3.74 (s, 3H), 3.39 (s, 3H), 0.91 (s, 9H), 0.13 (s, 3H), 0.13 (s, 3H); 13C
(b) Y. Kobayashi, H. Kamisaki, H. Takeda, Y. Yasui, R. Yanada, Y. Takemoto,
Tetrahedron 63 (2007) 2978e2989;
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2589e2592;
NMR (126 MHz, CDCl3, d) 169.8, 168.6, 158.9, 137.5, 134.0, 132.8,
130.3, 128.8, 128.4, 127.9, 127.8, 113.5, 73.2, 71.4, 69.4, 66.6, 62.3,
(f) Y. Yasui, H. Kamisaki, T. Ishida, Y. Takemoto, Tetrahedron 66 (2010)
1980e1989.
55.2, 52.0, 44.3, 25.8, 18.4, ꢀ0.1, ꢀ5.7; IR (ATR) 3366, 1670 cmꢀ1
;
HRMS (FABþ) C30H42NO7Si: (MHþ) 556.2731. Found 556.2731.
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(2004) 5580e5588 For examples, see;
3.1.3. Analytical data for lactam 10c
1H NMR (500 MHz, CDCl3,
d) 7.25 (d, 2H, J ¼ 8.8 Hz), 6.88 (dd,1H,
(b) Y. Tsuji, S. Yoshii, T. Ohsumi, T. Kondo, Y. Watanabe, J. Organomet. Chem.
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J1 ¼ J2 ¼ 6.4 Hz), 6.84 (d, 2H, J ¼ 8.8 Hz), 4.84 (s, 1H), 4.65 (s, 2H),
4.56 (d, 2H, J ¼ 5.2 Hz), 4.06 (d, 1H, J ¼ 12.2 Hz), 3.93 (d, 1H,
J ¼ 12.2 Hz), 3.79 (s, 3H), 3.53 (d, 1H, J ¼ 11.9 Hz), 3.38 (s, 3H), 3.10
(d, 1H, J ¼ 11.9 Hz), 1.36 (s, 6H), 0.92 (s, 9H), 0.10 (s, 3H), 0.098 (s,
(f) L.J. Gooben, J.E. Rauhaus, G. Deng, Angew. Chem. Int. Ed. 44 (2005)
3H); 13C NMR (126 MHz, CDCl3,
d) 168.0, 159.1, 139.4, 128.9, 114.1,
4042e4045;
98.8, 94.0, 71.0, 62.8, 62.2, 60.3, 55.6, 55.2, 43.2, 26.4, 25.8, 20.5,
18.2, ꢀ5.35, ꢀ5.39; IR (ATR) 1692 cmꢀ1; HRMS (FABþ) C27H43NO7Si:
(Mþ) 521.2809. Found 521.2789.
(g) D.C.D. Nath, C.M. Fellows, T. Kobayashi, T. Hayashi, Aust. J. Chem. 59 (2006)
218e224;
(h) L.J. Goo
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3.1.4. Analytical data for lactam 13a
1H NMR (500 MHz, CDCl3,
d
) 7.25 (d, 2H, J ¼ 8.9 Hz), 6.84 (d, 2H,
J ¼ 8.9 Hz), 6.83 (t, 1H, J ¼ 14.7 Hz), 4.83 (s, 1H), 4.66 (s, 2H), 4.55 (s,
2H), 4.09 (d, 1H, J ¼ 12.2 Hz), 3.94 (d, 1H, J ¼ 12.2 Hz), 3.79 (s, 3H),