Organocatalytic enantioselective Mannich-type reaction of phosphorus ylides: Synthesis of chiral N-Boc-β-amino-α-methylene carboxylic esters

Article abstract of DOI:10.1021/ja7114844

The first asymmetric Mannich-type reaction of stabilized phosphorus ylides and N-Boc aldimines was described promoted by a readily available and recyclable chiral bisthiourea organocatalyst. Subsequent reaction with formalin smoothly provides N-Boc-β-amino-α-methylene carboxylic esters in a highly enantiomerically enriched form (up to 96% ee). Copyright

Full text of DOI:10.1021/ja7114844

Published on Web 02/02/2008
Organocatalytic Enantioselective Mannich-Type Reaction of Phosphorus
Ylides: Synthesis of Chiral N-Boc-â-Amino-r-methylene Carboxylic Esters
Yan Zhang,† Yan-Kai Liu,† Tai-Ran Kang,† Ze-Kai Hu,† and Ying-Chun Chen*,†,‡
Key Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal Chemistry, West China
School of Pharmacy, Sichuan UniVersity, Chengdu 610041, China, and State Key Laboratory of Biotherapy,
West China Hospital, Sichuan UniVersity, Chengdu, China
Received December 30, 2007; E-mail: ycchenhuaxi@yahoo.com.cn
Scheme 1. A Novel Approach to Chiral â-Amino-R-methylene
â-Amino carbonyl compounds containing an R-alkylidene group
are highly densely functionalized materials which are widely applied
in the synthesis of medicinal reagents and natural products.1 They
are usually prepared through the classic aza-Morita-Baylis-
Hillman (MBH) reaction of activated imines and electron-deficient
alkenes catalyzed by tertiary amines or phosphines.2 Enormous
efforts have been devoted to this valuable process including its
asymmetric variant in the past decades, nevertheless, the aza-MBH
reaction remains to be restricted in substrate scope and enantio-
control.3 In addition, the nucleophilic catalysts typically utilized in
aza-MBH reactions may induce product racemization.4 Here we
would like to report the development of a novel but facile strategy
to the enantioselective synthesis of N-Boc-â-amino-R-methylene
carboxylic esters.5
Carbonyl Compounds
Table 1. Screening Studies of Organocatalytic Mannich-type
Reaction and Subsequent Synthesis of
N-Boc-â-amino-R-methylene Carboxylic Estersa
Stabilized phosphorus ylides (P-ylides) have previously been
shown to be good nucleophiles. Aside from the traditional Wittig
reaction with carbonyl compounds, P-ylides also found uses in
alkylation reactions.6 Nevertheless, their potential application as
versatile synthons in asymmetric synthesis has not been addressed
yet.7 We envisaged that P-ylides could act as competent nucleophilic
species to attack appropriately activated imines, and the function-
alized P-ylides with a chiral center would be generated after proton
transfer. Following the reaction with formaldehyde should provide
the desired â-amino-R-methylene carbonyl products (Scheme 1).
In light of the above consideration, the reaction of P-ylide 2a
and N-Boc imine 3a was initially investigated in toluene at room
temperature without any catalyst. Gratifyingly, the expected P-ylide
4a (R ) Et) could be isolated as a relatively stable compound, and
aza-MBH product 5a (R ) Et) was cleanly obtained after reaction
with formalin (Table 1, entry 1).8 Then we were inspired to explore
the possible asymmetric Mannich-type reaction of 2a and 3a
catalyzed by chiral Brønsted acids at 0 °C (see Figure 1).9 While
low ee values were obtained with catalysis by various phosphoric
acids10 after conversion to 5a (entries 2-4),11 thiourea 1d also gave
poor chiral induction (entry 5).12,13 Moderate ees were received
when new thioureas 1e-g were applied (entries 6-8). To our
delight, much better enantioselectivity was attained by employing
the easily available bisthiourea 1h (entry 9).14 As a result, the
concerted hydrogen bonding interaction of 2a and 3a with two
thiourea functional groups might be responsible for the higher
enantiocontrol in the Mannich-type reaction step.15 Ylides 2b and
2c, differing at the ester functionality, led to lower enantioselectivity
(entries 10 and 11). Later the reaction was conducted at lower
temperature to improve the enantioselectivity, and in general more
reliable results could be obtained when 4a was previously isolated
before quenching with HCHO.16 Superior results were observed in
m-xylene (entry 12 vs 13). Bisthiourea 1i and 1j provided identical
enantioselectivities compared to 1h (entries 14 and 15). In addition,
the stabilized P-ylides containing a ketone carbonyl exhibited much
entry
catalyst
2
solvent
yieldb (%)
eec (%)
1d
2
3
4
5
6
7
8
9
10
11
12f
13f
14f
15f
-
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2a
2a
2a
2a
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
m-xylene
m-xylene
m-xylene
5a-53
5a-62
5a-75
5a-60
5a-84
5a-80
5a-69
5a-62
5a-62
5b-77
5c-51
5a-89
5a-87
5a-71
5a-87
-
31
45
12
15
63
73
57
80
77e
52
83
89
89
89
1a
1b
1c
1d
1e
1f
1g
1h
1h
1h
1h
1h
1i
1j
a Unless noted otherwise, reactions were performed with 0.1 mmol of
2, 0.15 mmol of 3a, 10 mol % of 1, 40 mg 4 Å MS in 0.5 mL solvent at
0 °C for 24 h. Then excess HCHO was added and stirred at room temp for
another 24 h. b Isolated yield for two steps. c Determined by chiral HPLC
analysis. d At room temp for 48 h. e The absolute configuration was
determined by converting 5b to a known compound.3c f At -20 °C for 60
h, and then 4a was isolated before treating with formalin in THF for 24 h.
lower reactivity with N-Boc imines under the current catalytic
system. Attempts to synthesize â-substituted derivatives3g,5 with
aldehydes other than HCHO failed owing to the steric hindrance
of the chiral P-ylide 4a and its instability to refluxing THF.6c Such
problems remain to be further explored.17
Consequently, the tandem Mannich-type/Wittig reaction for the
synthesis of diverse chiral N-Boc-â-amino-R-methylene carboxylic
esters was investigated with 2a and a variety of N-Boc aldimines
catalyzed by 10 mol % of bisthiourea 1h. As demonstrated in Table
2, the reaction sequence showed substantial generality resulting in
broad substrate scope. Excellent enantioselectivities with good
† West China School of Pharmacy.
‡ West China Hospital.
9
2456
J. AM. CHEM. SOC. 2008, 130, 2456-2457
10.1021/ja7114844 CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Supporting Information Available: Experimental procedures,
structural proofs. This material is available free of charge via the Internet
at http://pubs.acs.org.
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Figure 1. The structures of chiral Brønsted acid catalysts.
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benzaldimine (entry 14). It was noteworthy that catalyst 1h could
be recovered by FC and reused in the Mannich-type reaction without
any effects on its efficacy (for 5a, second use, 81% yield, 89% ee;
third use, 85% yield, 90% ee).
In conclusion, we have presented the first asymmetric Mannich-
type reaction of stabilized phosphorus ylides and Boc-protected
aldimines by employing readily available and recyclable bisthiourea
organocatalysts. Subsequent reaction with formaldehyde provides
a facile access to chiral N-Boc-â-amino-R-methylene carboxylic
esters in good to excellent enantioselectivities. This methodology
presented herein may potentially open avenues for the application
of phosphorus ylides in asymmetric synthesis. Currently mechanism
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Acknowledgment. We are grateful for the financial support
from NSFC (20502018), Education of Ministry (NCET-05-0781),
and Sichuan Province Government (07ZQ026-027).
JA7114844
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