α-Amino Aldehydes as Readily Available Chiral Aldehydes for Rh-Catalyzed Alkyne Hydroacylation

Article abstract of DOI:10.1021/jacs.5b11892

Readily available α-amino aldehydes, incorporating a methylthiomethyl (MTM) protecting group on nitrogen, are shown to be efficient substrates in Rh-catalyzed alkyne hydroacylation reactions. The reactions are performed under mild conditions, employing a small-bite-angle bis-phosphine ligand, allowing for good functional group tolerance with high stereospecificity. Amino aldehydes derived from glycine, alanine, valine, leucine, phenylalanine, isoleucine, serine, tryptophan, methionine, and cysteine were successfully employed, as was an enantiomerically enriched α-OMTM-aldehyde derived from phenyllactic acid. The synthetic utility of the α-amino enone products is demonstrated in a short enantioselective synthesis of the natural product sphingosine.

Full text of DOI:10.1021/jacs.5b11892

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Article
#-Amino Aldehydes as Readily Available Chiral
Aldehydes for Rh-Catalyzed Alkyne Hydroacylation
Joel F. Hooper, Sangwon Seo, Fiona R. Truscott, James D. Neuhaus, and Michael C. Willis
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b11892 • Publication Date (Web): 15 Jan 2016
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α-Amino Aldehydes as Readily Available Chiral Aldehydes for Rh-
Catalyzed Alkyne Hydroacylation
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Joel F. Hooper,† Sangwon Seo,† Fiona R. Truscott, James D. Neuhaus and Michael C. Willis*
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA,
UK.
ABSTRACT: Readily available α-amino aldehydes, incorporating a methylthiomethyl (MTM) protecting group on nitro-
gen, are shown to be efficient substrates in Rh-catalyzed alkyne hydroacylation reactions. The reactions are performed
under mild conditions, employing a small-bite-angle bis-phosphine ligand, allowing for good functional group tolerance
and with high stereospecificity. Amino aldehydes derived from glycine, alanine, valine, leucine, phenylalanine, isoleucine,
serine, tryptophan, methionine and cysteine were successfully employed, as was an enantiomerically enriched α-OMTM-
aldehyde derived from phenyl lactic acid. The synthetic utility of the α-amino enone products is demonstrated in a short
enantioselective synthesis of the natural product sphingosine.
erties that result in amino groups being so prevalent in
INTRODUCTION
bioactive molecules.18
Alkene and alkyne hydroacylation reactions represent
The α-amino carbonyl motif is present in a number of
powerful methods for the preparation of ketones and
medicinal agents and natural products (Scheme 1),19 and
enones, respectively.1 These processes offer an atom eco-
features in intermediates for the synthesis of heterocycles
nomical and, in many cases, highly efficient method for
and in particular, enantiomerically enriched amino alco-
the construction of carbon-carbon bonds using a variety
hols.20 To target these important structures we were at-
of transition metal and also non-metal catalysts.2 Reac-
tracted to the use of naturally occurring α-amino acids as
tions that achieve high levels of regio- and enantioselec-
a readily available feedstock for chiral amino aldehydes to
tivity have been developed,3,4 and applications to target
use in HA reactions (eq 1, Scheme 1). Although enantiose-
synthesis are being reported.5
lective HA reactions have been reported,4 examples of
enantioenriched aldehydes being employed as substrates
Despite the advent of a number of non-chelation con-
trolled hydroacylation processes,6-9 the sub-class of in-
termolecular hydroacylation (HA) reactions that has en-
joyed most success, is that based on some form of sub-
strate chelation, be it originating from the aldehyde,10-14 or
alkene or alkyne.15 A consequence of such a strategy is
that the coordinating group needed to achieve the desired
reactivity and selectivity is necessarily present in both the
substrate and the product. Methods that utilize the coor-
dinating group directly in a subsequent transformation,
resulting in “traceless” processes, go someway to address-
ing these limitations.16 However, a more attractive scenar-
io would be one in which the coordinating group was a
simple, useful substituent the presence of which would be
desired in the final product. In this context, the ability to
exploit a simple amino-group would be appealing. Alt-
hough aniline-derived benzaldehyde-type substrates have
recently been reported as effective substrates for intermo-
lecular HA reactions, by both us,17a and others,17b these
substrates by their nature are limited to aromatic exam-
ples. Alkyl aldehydes featuring amino-substituents are
notable by their absence in the HA literature, presumably
a consequence of their strong-coordinating ability and
basic character. Conversely, these are precisely the prop-
in intermolecular reactions are scarce.15a,21 Given the mild
reaction conditions employed with our recently reported,
highly active small-bite-angle catalysts,22 we were confi-
dent that we should be able to maintain the enantiomeric
purity of such aldehydes in HA reactions. In this Article
we show that it is possible to utilize α-amino-substituted
alkyl aldehydes in HA reactions, and describe the applica-
tion of chiral α-amino aldehydes as effective substrates
for the synthesis of synthetically appealing chiral α-amino
enones.
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[Rh(nbd)2]BF4 (5 mol%)
dcpm (5 mol%)
R
N
O
R
N
O
Scheme 1. The α-amino ketone motif in biologically
relevant molecules, together with a Rh-catalyzed
hydroacylation route exploiting amino acids to ac-
cess α-amino enones (eq 1).
C6H13
1
2
3
4
5
6
7
8
Cbz
H
Cbz
C6H13
acetone, 55 °C
1a, R = H
1b, R = MOM
2a, R = H, traces
2b, R = MOM, traces
MeS
R
MeS
R
[Rh(nbd)2]BF4 (5 mol%)
O
O
C6H13
dcpm (5 mol%)
O
N
O
N
C6H13
4a, R = Cbz, 92%
4b, R = Ts, 70%
NHMe
H
O
acetone, 55 °C
Me
Me
Amfepramone
3a, R = Cbz
3b, R = Ts
N
N
F
Cl
Me
Ketamine
(anaesthetic)
With the key reactivity principle in place, we next ex-
plored the scope of the alkyne component in combination
with aldehyde 3a (Table 1). In all cases, a catalyst generat-
ed from the combination of [Rh(nbd)2]BF4 and the bis-
phosphine ligand dcpm, was employed. Both linear and
branched aliphatic alkynes (entries 1 - 3) as well as carbo-
cyclic alkynes (entries 4 and 5) could be employed. Aro-
matic alkynes, including a 3-thiophene example, were
excellent substrates (entries 6, 7 and 8), giving the enone
products in high yields. The exceptional functional group
tolerance of this reaction was demonstrated through the
use of a ferrrocenyl (entry 9), enyne (entry 10), alkyl io-
dide (entry 11) and unprotected alcohol (entry 12) sub-
strates, all giving the corresponding products in good
yields.
9
(appetite suppressant)
O
S
O
10
11
12
13
14
15
16
17
18
19
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O
H
NH2
O
Ph
N
N
Me
Me
CO2H
O
O
Ph
Effient
(antiplatelet)
Cathinone
(amphetamine)
Keto-ACE (hypertension)
O
O
O
R
Rh(I) cat.
R
R
R1 (1)
H
OH
R1
N
N
NH2
R2
PG
R2
PG
α-amino enones
α-amino acids
hydroacylation
abundant feedstock, chiral,
diverse substituents
mild reaction conditions,
functional group tolerant
valuable synthetic
building block
RESULTS AND DISCUSSION
We have previously shown that non-chiral α-hydroxy
aldehydes could be effectively employed in HA reactions
provided that the alcohol was protected as a methylthi-
omethyl (MTM) ether.23 We postulated that the corre-
sponding MTM-protected amino aldehydes should also
be viable HA substrates, with the MTM-group functioning
as a simple, removable, chelating-substituent. Using a
glycine derivative, we quickly established that both a
MTM group and an electron-withdrawing protecting
group were necessarily to achieve reactivity (Scheme 2).
For example, aldehyde 1a, featuring only a Cbz-protecting
group on the amine, was essentially inert in a reaction
with 1-octyne and a Rh(I)/dcpm catalyst, delivering only
trace quantities of the desired HA adduct (2a). Aldehyde
1b, combining a Cbz-group with a MOM-group on the N-
atom, was similarly unreactive. For both of these sub-
strates the majority of the starting aldehydes were recov-
ered, suggesting that reductive-decarbonylation generates
a non-active Rh-complex. However, aldehydes 3a and 3b,
featuring a MTM-group and either a Cbz or Ts group,
respectively, delivered the desired enones (4a,b) in good
yields. We attribute the success of the MTM-bearing al-
dehydes to the S-atom both directing the Rh-complex to
the aldehyde C-H bond for rapid oxidative addition, and
also stabilising the resultant acyl rhodium hydride inter-
mediate towards reductive-decarbonylation.22a,b The cor-
responding aldehyde bearing only a MTM group, but
without an accompanying electron-withdrawing group
was unstable and could not be isolated in pure form.
Table 1. Alkyne scope in hydroacylation reactions
with aldehyde 3a.a
[Rh(nbd)2]BF4 (5 mol%)
MTM O
N
MTM O
N
R
dcpm (5 mol%)
Cbz
H
Cbz
R
acetone, 55 °C
3a
4c-n
entry
1
alkyne
Me
yield
entry
7
alkyne
yield
99%
OMe
94%
Me
Ph
S
2
3
73%
80%
8
9
76%
93%
Me
Fe
Me
4
5
87%
75%
99%
10
11
75%
86%
71%
I
3
Me
6
12
OH
a
Reaction conditions: 3a (1.0 equiv), alkyne (1.5 equiv),
[Rh(nbd)2]BF4 (5 mol%), dcpm (5 mol%), acetone, 55 °C.
The reaction between glycine-derived aldehyde 3a and
5-pentynol proceeded smoothly; however, the product
isolated was tetrahydrofuran-substituted ketone 4o, re-
sulting from intramolecular conjugate addition of the
hydroxyl group into the initially formed enone (equation
2).
Scheme 2. Initial evaluation of glycine-derived alde-
hydes 1a,b and 3a,b in alkyne hydroacylation.
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substituted alkyne, as well as propargyl alcohol, while
1
2
3
4
5
6
7
8
9
maintaining high er vaues (8i,j). The hydroxyl-substituted
enone 8j, derived from phenylalanine and propargyl alco-
hol, has the connectivity and carbon back-bone featured
in Keto-ACE (Scheme 1). Employing an isoleucine-derived
aldehyde, hydroacylation was achieved with 1-octyne, as
well as a 3-thiophene-substituted alkyne (8k,l). The func-
tional group tolerance of this reaction was further
demonstrated by the use of the N-methyltryptophan al-
dehyde, giving the enantiopure hydroacylation products
with alkyl and TMS-substituted alkynes (8m,n). Pleasing-
ly, the reaction was also compatible with internal alkynes,
furnishing the expected products in good yields and as
single regioisomers (8o,p). Unfortunately, alkenes and
allenes show only poor reactivity with this class of alde-
hyde.
Having established mild and effective conditions for
alkyne hydroacylation using MTM-protected amino alde-
hydes, we next focused on access to enantiomerically pure
substrates. Initial attempts to MTM protect Cbz-leucine
methyl ester resulted in racemization (Scheme 3). How-
ever, by switching to the Weinreb amide substrate 5a, the
MTM-protected product (6a) could be prepared in excel-
lent yield, and following reduction with Dibal-H delivered
the aldehyde 7a in 99% yield with an excellent >99:1 en-
antiomeric ratio. This method was then applied to a varie-
ty of amino acid substrates. The aldehydes prepared were
typically used without purification, although all of the
aldehydes obtained were assayed (HPLC) for enantiopuri-
ty, and were shown to possess enantiomeric ratios of at
least 98:2. The phenylalanine derived aldehyde (7f) was
found to be less chemically stable than the other alde-
hydes and also to be more labile to racemization; howev-
er, with care, an er of 99:1 could be achieved.
10
11
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Table 2. Hydroacylation reactions of amino acid de-
rived enantiomerically enriched aldehydes.a
O
O
R1
R1
[Rh(nbd)2]BF4 (5 mol%)
dcpm (5 mol%)
R3
R3
H
R2
MTM
8a-n
N
N
R2
acetone, 55 °C, 3 h
PG
MTM
PG
7
Scheme 3. Synthesis of the enantiomerically enriched
Me
Me
Me
N
Me
Me
Me
α-amino aldehydes.
O
O
O
C6H13
C6H13
C6H13
Me
Me
Me
Me
O
O
N
N
NaHMDS
Cbz
MTM
Teoc
MTM
8b, 96%
>99:1 er, 100% es
Boc
MTM
MTM-Cl, NaI
OMe
OMe
8a, 82%
99:1 er, 98% es
8c, 90%
50:50 er
>99:1 er, 100% es
NH
Me
DMF
N
Cbz
Me
Cbz
Cbz
MTM
Me
Me
Me
O
Me
O
O
Me
Me
N
Me
Me
Me
O
O
O
C6H13
NaHMDS
MTM-Cl, NaI
OMe
OMe
N
N
N
Dibal-H
toluene
-78 °C, 99% Cbz
N
H
N
Cbz
MTM
Cbz
MTM
Cbz
MTM
DMF, 88%
NH Me
5a
Me
N
8d, 73%
8e, 84%
8f, 87%
Cbz
MTM
MTM
99:1 er, 99% es
99:1 er, 99% es
>99:1 er, 100% es
O
6a
7a, >99:1 er
O
Me
O
Me
Me
Me
Me
Me
Me
Ph
Cbz
C6H13
Ph
Me
Cbz
C6H13
O
O
O
Me
O
N
N
N
Me
Me
MTM
MTM
Cbz
H
H
H
Me
Cbz
H
MTM
8i, 84%
98.5:1.5 er, 99% es
N
N
N
N
8g, 89%
8h, 85%
Teoc
MTM
Boc
MTM
Cbz
MTM
MTM
>99:1 er, 100% es
98.5:1.5 er, 99% es
7e, >99:1 er
7d, >99:1 er
7c, >99:1 er
7b, >99:1 er
Me
O
O
Me
O
O
Me
C6H13
OH
Me
O
Me
O
Ph
Cbz
S
Me
H
MTM
7h, >99:1 er
N
N
N
Ph
H
H
Cbz
MTM
MTM
Cbz
MTM
N
N
N
N
Cbz
Cbz
MTM
Cbz
MTM
Me
8j, 60%
8k, 79%
8l, 67%
98:2 er, 97% es
97:3 dr, 98% ds
98:2 dr, 100% ds
7f, 99:1 er
7g, 98:2 dr
O
O
C6H13
SiMe3
With a simple and robust synthesis of MTM-protected
N
N
N
N
Cbz
α-amino aldehydes established, we next examined the use
of these molecules in hydroacylation reactions with vari-
ous alkynes (Table 2). Starting from leucine, the Cbz-
Boc- and Teoc-protected aldehydes were combined with
1-octyne to give the hydroacylation products in excellent
yields and with enantiometic ratios of 99:1 or higher (8a-
c). These high er values correlate with enantiospecificities
(es) in the range of 95-100%.24 The Cbz-leucine substrate
was effectively combined with phenylacetylene and a cy-
clopropyl-alkyne (8d,e). The alanine, valine and phenyl-
alanine derived aldehydes were all combined with 1-
octyne without incident (8f-h). In addition, the phenylal-
Cbz
MTM
MTM
Me
Me
8m, 86%
8n, 82%
>99:1 er, 100% es
Me Me
99:1 er, 99% es
Me
Me
O
O
Et
Et
MTM
Me
N
N
Cbz
Cbz
MTM
8o, 92%
98:2 er, 96% es
8p, 73%
97:3 er, 95% es, >20:1 rr
a
Reaction conditions: aldehyde (1.0 equiv), alkyne (1.5
equiv), [Rh(nbd)2]BF4 (5 mol%), dcpm (5 mol%), acetone, 55
°C, 3 h. es values were calculated using raw HPLC data, ra-
ther than the rounded er values reported above.
t
anine substrate was also partnered with the bulky Bu-
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Me
Me
Me
Me
In addition to employing amino aldehyde substrates
bearing a MTM group, we were also able to exploit the
chelating ability of S-methyl cysteine, and methionine-
derived aldehydes, 9 and 10, respectively (Scheme 4). In
both cases, hydroacylation of the MTM-free aldehydes
was achieved using the dcpm-derived catalyst in combi-
nation with octyne. The methionine-derived substrate
required a higher catalyst loading (10 mol%). This re-
duced reactivity is consistent with our previous report of
aliphatic γ-substituted thiomethyl-aldehydes, and again
suggests that the MTM-bearing substrates benefit from a
conformational arrangement that promotes chelation.23
Following on from this, the MTM-protected α-hydroxy
aldehyde 11, derived from phenyl lactic acid, delivered the
hydroacylation adduct 14 in excellent yield as a single
enantiomer.
O
O
BF3.OEt2
CH2Cl2
1
2
3
4
5
6
7
8
C6H13
C6H13
N
NH
Cbz
MTM
Cbz
15a, 83%, 98.5:1.5 er, 99% es
8a
Me
Me
Me
Me
O
O
TBAF
THF
C6H13
C6H13
HN
N
MTM
15b, 85%, >99:1 er, 100% es
Teoc
MTM
8b
9
AgNO3
2,6-lutidine
THF/H2O
Me
Me
Me
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
then TFA
C6H13
C6H13
-
+
CF3CO2
NH3
N
Boc
MTM
8c
15c, 95%, >99:1 er, 100% es
As a demonstration of the utility of the MTM-directed
hydroacylation reactions of enantiomerically enriched α-
amino aldehydes, we applied this method to a short enan-
tio and diastereoselective synthesis of the natural product
sphingosine (Scheme 6). The key MTM/Cbz-protected,
serine-derived amino aldehyde 16 was available as before,
by Dibal-H reduction of the corresponding Weinreb am-
ide in good yield and with a 99:1 er. Hydroacylation of 16
proceeded smoothly on a gram scale using only 2 mol%
catalyst loading, affording enone 17 in 94% yield with no
loss in the enantiopurity (99:1). Selective MTM deprotec-
tion was achieved by first converting to the hydroxyme-
thyl group (AgNO3, 2,6-lutidine, THF/H2O, rt), and its
subsequent thermal decomposition (reflux in toluene) to
provide carbamate 18 (98:2 er). Literature precedent25
Scheme 4. Hydroacylation of cysteine, methionine
and phenyl lactate derived aldehydes.
[Rh(nbd)2]BF4
(5 mol%)
O
O
C6H13 dcpm (5 mol%)
MeS
C6H13
MeS
H
+
NH
NH
acetone, 55 °C, 3 h
Cbz
Cbz
9, >99:1 er
12, 75%
99:1 er, 98% es
[Rh(nbd)2]BF4
(10 mol%)
C6H13 dcpm (10 mol%)
acetone, 55 °C, 3 h
O
O
MeS
MeS
H
+
C6H13
NH
NH
Cbz
Cbz
13, 63%
10, >99:1 er
97:3 er, 94% es
[Rh(nbd)2]BF4
(5 mol%)
O
O
dcpm (5 mol%)
C6H13
Ph
C6H13
Ph
H
using
LiAl(OtBu)3H
allowed
excellent
anti-
+
acetone, 55 °C, 3 h
OMTM
OMTM
diastereoselective reduction of ketone 18 to alcohol 19 in
good yield. Finally, treating 19 with NaOH and heating in
MeOH/H2O led to one-pot TBS and Cbz deprotection,
and afforded sphingosine 20. The MTM-directed hy-
droacylation not only established an efficient and com-
petitive route to this natural product, but the mild reac-
tion conditions also allowed the straightforward prepara-
tion of several tagged-derivatives. For example, hydroac-
ylation of aldehyde 16 with functionalized alkynes afford-
ed fluorophore 21a,26a electrochemically active organome-
tallic 21b26b and alkyne 21c (suitable for Huisgen cycload-
dition chemistry),26c in good yields.
14, 79%
>99:1 er, 100% es
11, >99:1 er
The variation possible in the identity of the electron-
withdrawing groups on the nitrogen atom of the amino
aldehydes allows flexibility with regard to N-deprotection
strategies and corresponding reagent choice; three exam-
ple transformations are shown below (Scheme 5). Treat-
ment of the Cbz-protected hydroacylation product 8a
with BF3.OEt2 allowed for the selective removal of the
MTM group (15a). Alternatively, the carbamate could be
removed in the presence of the MTM group by treating
the Teoc-derivative with TBAF (8b → 15b). The use of a
Boc group allowed for a double deprotection; treatment
with AgNO3 and then TFA delivered the ammonium tri-
fluoroacetate salt (8c → 15c). Importantly, enantiomeric
ratios were conserved throughout these protecting group
manipulations.
Scheme 6. Application to the synthesis of sphingo-
sine (20), together with the preparation of example
tagged derivatives (21a-c).
Scheme 5. Example deprotection possibilities for hy-
droacylation products.
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C13H27
O
* michael.willis@chem.ox.ac.uk
O
2 mol% [Rh(nbd)2]BF4
2 mol% dcpm
† These authors contributed equally to this work.
1
2
3
TBSO
Cbz
C13H27
TBSO
Cbz
H
N
acetone, 55 °C
(1.3 g scale)
N
MTM
MTM
16, 99:1 er
ACKNOWLEDGMENT
17, 94%, 99:1 er, 100% es
4
5
6
7
8
9
This work was supported by the EPSRC.
AgNO3, 2,6-lutidine
then tol. 120 °C
THF/H2O, rt
TBSO
REFERENCES
1. (a) Willis, M. C.; Chem. Rev. 2010, 110, 725. (b) Jun, C.-H.; Jo,
E.-A.; Park, J.-W. Eur. J. Org. Chem. 2007, 1869.
2. Selected examples: (a) Schedler, M.; Wang, D.-S.; Glorius, F.
Angew. Chem. Int. Ed. 2013, 52, 2585. (b) Bugaut, X.; Liu, F.;
Glorius, F. J. Am. Chem. Soc. 2011, 133, 8130.
OH
O
LiAl(OtBu)3H
TBSO
C13H27
C13H27
EtOH, -78 o
C
NH
NH
Cbz
19, 93%, >99:1 dr
Cbz
18, 91%, 98:2 er, 98% es
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
MeOH/H2O, 80 o
C
NaOH
3. Intermolecular examples: (a) Jun, C.-H.; Lee, H.; Hong, J.-B.;
Kwon, B.-I. Angew. Chem. Int. Ed. 2002, 41, 2146. (b) Gonzá-
lez-Rodríguez, C.; Pawley, R. J.; Chaplin, A. B.; Thompson, A.
L.; Weller, A. S.; Willis, M. C. Angew. Chem. Int. Ed. 2011, 50,
5134. (c) Zhang, H.-J.; Bolm, C. Org. Lett. 2011, 13, 3900. (d)
Chen, Q.-A.; Cruz, F. A.; Dong, V. M. J. Am. Chem. Soc. 2015,
137, 3157.
4. Intermolecular examples: (a) Stemmler, R. T.; Bolm, C. Adv.
Synth. Catal. 2007, 349, 1185. (b) Osborne, J. D.; Randell-Sly,
H. E.; Currie, G. S.; Cowley, A. R.; Willis, M. C. J. Am. Chem.
Soc. 2008, 130, 17232. (c) Shibata, Y.; Tanaka, K. J. Am. Chem.
Soc. 2009, 131, 12552. (d) Inui, Y.; Tanaka, M.; Imai, M.;
Tanaka, K.; Suemune, H. Chem. Pharm. Bull. 2009, 57, 1158.
(e) Coulter, M. M.; Kou, K. G. M.; Galligan, B.; Dong, V. M. J.
Am. Chem. Soc. 2010, 132, 16330. (f) Phan, D. H. T.; Kou, K. G.
M.; Dong, V. M. J. Am. Chem. Soc. 2010, 132, 16354.
OH
20 (sphingosine), 97%
HO
C13H27
NH2
O
O
O
O
TBSO
N
11
Cbz
MTM
Me
21a, 84%, 97:3 er, 97% es
TBSO
Cbz
O
O
a
O
H
TBSO
Cbz
11
Fe
N
N
MTM
MTM
16, 99:1 er
21b, 76%, 98.5:1.5 er, 99% es
O
TBSO
11
5. von Delius, M.; Le, C. M.; Dong, V. M. J. Am. Chem. Soc.
2012, 134, 15022.
6. For a review, see: Leung, J. C.; Krische, M. J. Chem. Sci. 2012,
3, 2202.
N
Cbz
MTM
21c, 49%, 97:3 er, 96% es
a
Reagents: [Rh(nbd)2]BF4 (2 mol%), dcpm (2 mol%), and
appropriately tagged terminal alkyne (1.5 equiv).
7. Rh-catalysis: (a) Marder, T. B.; Roe, D. C.; Milstein, D. Or-
ganometallics 1988, 7, 1451. (b) Roy, A. H.; Lenges, C. P.;
Brookhart, M. J. Am. Chem. Soc. 2007, 129, 2082.
8. Ru-catalysis: (a) Kondo, T.; Akazome, M.; Tsuji, Y.;
Watanabe, Y. J. Org. Chem. 1990, 55, 1286. (b) Omura, S.; Fu-
kuyama, T.; Horiguchi, J.; Murakami, Y.; Ryu, I. J. Am. Chem.
Soc. 2008, 130, 14094. (c) Shibahara, F.; Bower, J. F.; Krische,
M. J. J. Am. Chem. Soc. 2008, 130, 14120. (d) Williams, V. M.;
Leung, J. C.; Patman, R. L.; Krische, M. J. Tetrahedron, 2009,
65, 5024. See also ref 3e.
CONCLUSIONS
In conclusion, we have developed a Rh(I)-catalyzed
MTM-directed hydroacylation of alkynes using enantio-
merically enriched α-amino aldehydes. The reaction is
highly functional group tolerant, delivering a wide range
of α-amino enones in excellent yields and with almost
complete retention of enantiopurities. This transfor-
mation has been used for the crucial C–C bond-forming
step in a concise synthesis of the natural product sphin-
gosine. MTM-Free aldehydes derived from S-methyl cys-
teine, and methionine, could also be employed in efficient
intermolecular alkyne HA reactions. The demonstration
of N-MTM groups functioning as efficient chelating units
provides an additional synthetically useful motif to ex-
ploit in intermolecular HA reactions.
9. Co-catalysis: (a) Lenges, C. P.; White, P. S.; Brookhart, M. J.
Am. Chem. Soc. 1998, 120, 6965. (b) Chen, Q.-A.; Kim, D. K.;
Dong, V. M. J. Am. Chem. Soc. 2014, 136, 3772.
10. O-Chelation: (a) Kokubo, K.; Matsumasa, K.; Miura, M.;
Nomura, M. J. Org. Chem. 1997, 62, 4564. (b) Imai, M.;
Tanaka, M.; Tanaka, K.; Yamamoto, Y.; Imai-Ogata, N.;
Shimowatari, M.; Nagumo, S.; Kawahara, N.; Suemune, H. J.
Org. Chem. 2004, 69, 1144. (c) Murphy, S. K.; Petrone, D. A.;
Coulter, M. M.; Dong, V. M. Org. Lett. 2011, 13, 6216.
11. S-Chelation: (a) Willis, M. C.; McNally, S. J.; Beswick, P. J.
Angew. Chem. Int. Ed. 2004, 43, 340. (b) Willis, M. C.;
Woodward, R. L. J. Am. Chem. Soc. 2005, 127, 18012. (c) Wil-
lis, M. C.; Randell-Sly, H. E.; Woodward, R. L.; McNally, S. J.;
Currie, G. S. J. Org. Chem. 2006, 71, 5291. (d) Lenden, P.;
Entwistle, D. A.; Willis, M. C. Angew. Chem. Int. Ed. 2011, 50,
10657. For an intramolecular example, see: (e) Bendorf, H.
D.; Colella, C. M.; Dixon, E. C.; Marchetti, M.; Matukonis, A.
N.; Musselman, J. D.; Tiley, T. A. Tetrahedron Lett. 2002, 43,
7031.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures and supporting characterization
data and spectra (pdf). “This material is available free of
charge via the Internet at http://pubs.acs.org.”
12. N-Chelation: (a) Suggs, J. W. J. Am. Chem. Soc. 1978, 100,
640. For in situ generated N-chelation: (b) Jun, C.-H.; Lee,
D.-Y.; Lee, H.; Hong, J.-B. Angew. Chem. Int. Ed. 2000, 39,
3070; and ref 3a.
AUTHOR INFORMATION
Corresponding Author
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13. P-Chelation: Lee, H.; Jun, C.-H. Bull. Korean Chem. Soc. 1995,
Chem. Lett. 2006, 16, 4612. (c) Jamora, C.; Iravani, M. Am. J.
Ther. 2010, 17, 511.
1
2
3
4
5
6
7
8
16, 66.
14. C-Chelation: Lochow, C. F.; Miller, R. G. J. Am. Chem. Soc.
1976, 98, 1281.
20. For example: (a) Bouteiller, C.; Becerril-Ortega, J.; Marchand,
P.; Nicole, O.; Barré, L.; Buisson, A.; Perrio, C. Org. Biomol.
Chem., 2010, 8, 1111. (b) Zhang, J.; Wang,Y.-Q.; Wang, X.-W.;
Li, W.-D. Z. J. Org. Chem. 2013, 78, 6154.
21. Kim, G.; Lee, E.-j, Tetrahedron Asym. 2001, 12, 2073.
22. (a) Chaplin, A. B.; Hooper, J. F.; Weller, A. S.; Willis, M. C. J.
Am. Chem. Soc. 2012, 134, 4885. (b) Pernik, I.; Hooper, J. F.;
Chaplin, A. B.; Weller, A. S.; Willis, M. C. ACS Catal. 2012, 2,
2779. (c) Prades, A.; Fernández, M.; Pike, S. D.; Willis, M. C.;
Weller, A. S. Angew. Chem. Int. Ed. 2015, 54, 8520.
23. Parsons, S. R.; Hooper, J. F.; Willis, M. C. Org. Lett. 2011, 13,
998.
24 Denmark, S. E.; Vogler, T.; Chem. Eur. J. 2009, 15, 11737.
25. (a) Hoffman, R. V.; Maslouh, N.; Cervantes-Lee, F. J. Org.
Chem. 2002, 67, 1045. (b) Yang H.; Liebeskind, L. S. Org. Lett.
2007, 9, 2993.
15. (a) Murphy, S. K.; Bruch, A.; Dong, V. M. Angew. Chem. Int.
Ed. 2014, 53, 2455. (b) Murphy, S. K.; Bruch, A.; Dong, V. M.
Chem. Sci. 2015, 6, 174. See also, refs 4c,d,e, 5, and 10b.
16. (a) Hooper, J. F.; Chaplin, A. B.; González-Rodríguez, C.;
Thompson, A. L.; Weller, A. S.; Willis, M. C. J. Am. Chem.
Soc. 2012, 134, 2906. (b) Hooper, J. F.; Young, R. D.; Weller,
A. S.; Willis, M. C. Chem. Eur. J. 2013, 19, 3125. (c) Hooper, J.
F.; Young, R. D.; Pernik, I.; Weller, A. S.; Willis, M. C. Chem.
Sci. 2013, 4, 1568.
17. (a) Castaing, M; Wason, S. L.; Estepa, B.; Hooper, J. F.; Willis,
M. C. Angew. Chem. Int. Ed. 2013, 52, 13280. (b) Zhang, T.; Qi,
Z.; Zhang, X.; Wu, L.; Li, X. Chem. Eur. J. 2014, 20, 3283. For a
related intramolecular ketone hydroacylation, see: (c) Khan,
H. A.; Kou, K. G. M.; Dong, V. M. Chem. Sci. 2011, 2, 407.
18. Bissantz, C.; Kuhn, B.; Stahl, M. J. Med. Chem. 2010, 53, 5061.
19. For example: (a) Meltzer, P. C.; Butler, D.; Deschamps, J. R.;
Madras, B. K. J. Med. Chem. 2006, 49, 1420. (b) Nchinda, A.
T.; Chibale, K.; Redelinghuys, P.; Sturrock, E. D. Bioorg. Med.
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
26. (a) Giepmans, B. N. G.; Adams, S. R.; Ellisman, M. H.; Tsien,
R. Y. Science 2006, 312, 217. (b) Marsh, B. J.; Hampton, L.;
Goggins, S.; Frost, C. G. New. J. Chem. 2014, 38, 5260. (c)
Kolb, H. C.; Sharpless, K. B. Drug Disc. Today 2003, 8, 1128.
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O
O
[Rh(nbd)2]BF4
R1
R1
R2
1
dcpm
R2
H
acetone, 55 °C
2
3
4
N
N
Cbz
MTM
Cbz
MTM
from natural amino acids
high er
high yield, high es
Me
Me
5
6
7
8
O
Me
O
O
Me
SiMe3
Et
S
N
N
Et
N
N
Cbz
MTM
Cbz
MTM
Cbz
MTM
Me
99:1 er
98:2 dr
98:2 er
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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