Rapid assembly of complex cyclopentanes employing chiral, α,β-unsaturated acylammonium intermediates

Article abstract of DOI:10.1038/nchem.1788

With the intention of improving synthetic efficiency, organic chemists have turned to bioinspired organocascade or domino processes that generate multiple bonds and stereocentres in a single operation. However, despite the great importance of substituted cyclopentanes, given their prevalence in complex natural products and pharmaceutical agents, the rapid, enantioselective assembly of these carbocycles lags behind cyclohexanes. Here, we describe a Michael-aldol-β-lactonization organocascade process for the synthesis of complex cyclopentanes utilizing chiral α,β-unsaturated acylammonium intermediates, readily generated by activation of commodity unsaturated acid chlorides with chiral isothiourea catalysts. This efficient methodology enables the construction of two C-C bonds, one C-O bond, two rings and up to three contiguous stereogenic centres delivering complex cyclopentanes with high levels of relative and absolute stereocontrol. Our results suggest that α,β-unsaturated acylammonium intermediates have broad utility for the design of organocascade and multicomponent processes, with the latter demonstrated by a Michael-Michael-aldol-β-lactonization.

Full text of DOI:10.1038/nchem.1788

ARTICLES
PUBLISHED ONLINE: 3 NOVEMBER 2013 | DOI: 10.1038/NCHEM.1788
Rapid assembly of complex cyclopentanes
employing chiral, a,b-unsaturated acylammonium
intermediates
Gang Liu†, Morgan E. Shirley†, Khoi N. Van, Rae Lynn McFarlin and Daniel Romo
*
With the intention of improving synthetic efficiency, organic chemists have turned to bioinspired organocascade or domino
processes that generate multiple bonds and stereocentres in a single operation. However, despite the great importance of
substituted cyclopentanes, given their prevalence in complex natural products and pharmaceutical agents, the rapid,
enantioselective assembly of these carbocycles lags behind cyclohexanes. Here, we describe a Michael–aldol-
b-lactonization organocascade process for the synthesis of complex cyclopentanes utilizing chiral a,b-unsaturated
acylammonium intermediates, readily generated by activation of commodity unsaturated acid chlorides with chiral
isothiourea catalysts. This efficient methodology enables the construction of two C–C bonds, one C–O bond, two rings and
up to three contiguous stereogenic centres delivering complex cyclopentanes with high levels of relative and absolute
stereocontrol. Our results suggest that a,b-unsaturated acylammonium intermediates have broad utility for the design of
organocascade and multicomponent processes, with the latter demonstrated by a Michael–Michael–aldol-b-lactonization.
ynthetic transformations that rapidly assemble complexity are is a highly versatile intermediate for a variety of transformations
actively being pursued given the importance of these processes including aldol-b-lactonizations20,27,28, a-halogenation29, a-amin-
S
for achieving improvements in synthetic efficiency. In this ation30, hetero Diels–Alder reactions31–33, Michael–lactonizations34
regard, domino1 and (most recently) organocascade2,3 processes and Michael–lactamizations35 (Fig. 2b). Another more recent
have emerged as some of the most useful strategies for quickly gen- member of this family of chiral intermediates is the ammonium die-
erating structural complexity4. Such methods for the construction of nolate 6, which is derived from g-deprotonation of an a,b-unsatu-
6-membered carbocycles are numerous and include a range of clas- rated acylammonium intermediate36. We anticipated generation of
sical methods with the Robinson annulation5 (for a designed orga- the unsaturated acylammonium 3 through catalytic, asymmetric acti-
nocascade process applied to the Robinson annulation, see ref. 6), vation of acid chlorides by a chiral amine nucleophile (Fig. 2c).
the cationic polyene olefin cyclization7 and the venerable Diels– Following Michael addition by an appropriate nucleophile (Nuc1),
Alder reaction8 serving as benchmarks. By contrast, the construc- a chiral ammonium enolate 7 is revealed, enabling a-addition of an
tion of 5-membered carbocycles falls short of such diverse and electrophile (E) to deliver the acylammonium 8, and regeneration
widely used methods. Several elegant strategies exist for 5-mem- of the amine catalyst by acyl substitution with a second nucleophile
bered carbocycle synthesis or annulations, including the Pauson– (Nuc2) would finally deliver the triply functionalized adduct 9
Khand reaction9, trimethylenemethane [3 þ 2] cycloaddition10, (Fig. 2c). If the reaction partners are tethered (dashed lines), a bicyclic
photochemical olefin–arene cycloaddition11 and the Nazarov cycli- adduct 9 would result. A seminal report by the Fu group in 2006
zation12, but most require designed substrates or lack general, enan- demonstrated the potential of unsaturated acylammonium catalysis
tioselective variants13. Organocatalytic methods for highly employing an unsaturated acyl fluoride and a chiral 4-pyrrolidinopyr-
substituted cyclopentane synthesis have begun to emerge, enabling idine derivative to deliver a net [3 þ 2] cycloaddition with a silylated
access to a variety of systems14–17; however, methods with greater indene with moderate enantioselectivities37. The fluoride released
scope and practicality are still needed. To address the challenge of during acyl substitution was required to increase the reactivity of
efficient enantioselective construction of stereochemically rich the allylsilane nucleophile. This remained the only report employing
cyclopentanes, a common motif in bioactive natural products18 this chiral intermediate until very recently, when the Smith group
and pharmaceuticals (Fig. 1a), we sought to design an organocas- reported the use of unsaturated, mixed anhydrides in combination
cade process that could rapidly assemble these carbocycles from with 1,3-dicarbonyl compounds to provide aryl-substituted enol lac-
readily available starting materials.
tones through an enantioselective, tandem Michael–enol-lactoniza-
Building on our previously described aldol-b-lactonization tion process38. It should be noted that in both of these previous
process19–21, we were attracted to the potential utility of chiral a,b- reports, the full potential of the latent, triply-reactive, unsaturated acyl-
unsaturated acylammonium intermediates 3 given the presence of ammonium 3 was not realized through the formation of three new
three disparate reactive sites that could be revealed sequentially to bonds. Here, we describe the development of a novel organocascade
induce tandem bond-forming events (Fig. 2a). Within nucleophilic process involving a nucleophile-catalysed, Michael–aldol-b-lactoni-
chiral amine catalysis22, chiral acylammonium intermediate 4, zation (NCMAL) sequence that rapidly generates stereochemically
which bears one electrophilic site, has proven exceedingly useful for complex cyclopentanes from commodity unsaturated acid chlorides
kinetic resolution of alcohols23–25. The chiral ammonium enolate including both fused and bridged cyclopentyl systems (Fig. 1c). As
5 (ref. 26), bearing a nucleophilic site and a latent electrophilic site, a consequence of the terminating lactonization step, the NCMAL
Department of Chemistry, Texas A&M University, PO Box 30012, College Station, Texas 77842-3012, USA, †These authors contributed equally to this work.
e-mail: romo@tamu.edu
*
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1788
ARTICLES
a
Me
OH
H
(CH2)3CO2H
O
HO
O
O
CO2Me
OH
H
H
HO
Me
H
OMe
H
O
Me
H
O
O
OH
H
HO
HO
H
H
Me
CO2H
O
(CH2)4CH3
O
Me
Prostacyclin (PGI2)
Rameswaralide
Chinesin II
Gibberellic acid
R
H
HO
Me
Me
O
H
H
H
H
CO2H
Me
Me
H
HO
OHC
Me
Me
14β-Estra-5(10),6,8-triene
-17α-carboxylic acid
OH
Aldovibsanin A
Foxamax
Me
Me
c
OC(O)CH2CH(CH3)2
b
O
O
Me
H
R
Me
OH
HO
O
R
O
O
O
O
CO2Me
ʹ
H
R
O
HO
Me
Me
O
H
n
Spongiolactone
Vibralactone A
(n = 1,2)
Me
Me
H
R
H
O
H
Me
H
Me
H
CO2H
ʹ
R
H
O
H
Me
ʹʹ
R
O
Me
O
Lupeolactone
Figure 1 | Natural products and pharmaceutical agents bearing complex cyclopentanes and accessible cyclopentyl systems employing the described
NCMAL process. a, Bioactive natural products and drugs including polycyclics possessing highly substituted cyclopentane cores (red). b, Natural products
possessing b-lactone-fused cyclopentanes and a cyclohexane (red). c, Several diverse cyclopentane scaffolds accessible by the described NCMAL process.
delivers b-lactone-fused cyclopentanes, a structural motif found in malonate 10a. Our initial reaction conditions involved generation
the natural products spongiolactone and vibralactone A (Fig. 1b) in of the malonate anion with various Brønsted bases in the presence
addition to a growing family of activity-based probes for proteome of a nucleophilic catalyst, followed by slow addition of the acid
profiling39. The NCMAL process was rendered enantioselective by chloride to the mixture. Use of the nucleophile alone or the
the use of chiral isothiourea nucleophilic catalysts40,41, leading to strong Brønsted base DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)
the asymmetric synthesis of cyclopentanes with up to three contigu- did not provide the desired bicyclic-b-lactone 14a (Table 1,
ous stereocentres including quaternary carbons.
entries 1, 2). However, the synergistic action of DBU and a Lewis
The envisioned catalytic cycle for the organocascade process acid (LiClO4, entry 3) afforded the desired product in 68% yield42.
would be initiated by an intermolecular Michael addition of a To ensure complete enolate formation, stronger lithium bases
tethered, triply-reactive reagent 11, such as anionic ketone 10, to were studied and found to provide a further improvement in
the a,b-unsaturated acylammonium intermediate 3. The key yields (entries 4–6), up to 75% yield. Use of more weakly coordinat-
chiral intermediate 3 would be derived from simple substitution ing counter ions such as sodium and potassium led to drastically
of a chiral amine catalyst (NR3) 2 with an unsaturated acid chloride lower yields (entries 7, 8), while magnesium afforded a comparable
1 (Fig. 2d). Generation of the versatile ammonium enolate 12 yield (entry 9). A brief screening of nucleophiles, including 9-azaju-
enables engagement of the pendant ketone in an intramolecular lolidine, revealed that 4-pyrrolidinopyridine (4-PPY) and LiHMDS
aldol-b-lactonization templated by a Li(I) cation to deliver a stereo- was an optimal combination for the NCMAL process (entries 10,
selective aldol reaction, leading to the formation of cyclopentane 13. 11). As evidence for the requirement of the nucleophile, a control
Based on our previous studies, high anti diastereoselectivity was reaction without 4-PPY did not afford any b-lactone (entry 12).
anticipated for b-substituted acid chlorides because this alleviates
the development of A1,3-strain during the aldol-lactonization step Scope of the racemic NCMAL with various Michael donors and
(see 12)20. A final b-lactonization would deliver the fused acceptors. With suitable conditions for the NCMAL process in
b-lactone ring and regenerate the nucleophilic amine catalyst.
hand, we investigated the effect of varying the Michael donors
(Table 2, left column, entries 1–9). Successful Michael donors
bore two electron-withdrawing groups, an important feature
Results and discussion
We first set out to identify a suitable Brønsted base to generate a pointing to the requirement of a soft enolate for the Michael
reactive Michael donor from the latent anionic reagent, keto addition. These substrates were obtained in a single step by
2
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1788
ARTICLES
a
*
O
Table 1 | Optimization of the racemic NCMAL process.
NR3
O
β
Unsaturated
acylammonium
catalysis
2
+
H
*
MeO2C
O
ʹ
R
NR3
O
ʹ
R
20 mol% catalyst
MeO2C
MeO2C
Cl
α
+
–
Cl
EtN(iPr)2 (2.0 equiv.)
MeO2C
O
Cl
1
3
O
Me
10a (1.0 equiv.)
1a (2.0 equiv.)
( )-14a
–
b
O
Entry
Base
Catalyst
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
THF/CH2Cl2 73
THF/CH2Cl2 75
THF/CH2Cl2 75
THF/CH2Cl2 23
THF/CH2Cl2 ,5
THF/CH2Cl2 75
THF/CH2Cl2 84
THF/CH2Cl2 77
THF/CH2Cl2 ,5
% yield*
–
O
O
ʹ
R
–
X
1
2
3
4
5
–
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
4-PPY
9-AJ†
,5
,5
68
γ
ʹʹ
NR3
+
α
DBU
NR3
+
NR3
+
ʹ
R
R
LiClO4 þ DBU
4
5
6
LDA
tBuLi
= Electrophilic site
= Nucleophilic site
= Chiral groups
*
6
7
LiHMDS
NaHMDS
KHMDS
iPrMgCl
LiHMDS
LiHMDS
LiHMDS
8
9
10
11
12
Nuc1
Nuc1
c
–
O
O
O
–
Cl
+
NR3
ʹ
+
R
ʹ
ʹ
R
Cl
R
NR3
+
–
E
1
*Refers to isolated yields. ,5% yield indicates that b-lactone was not detected by TLC, 1H NMR
(500 MHz), or Fourier-transform infrared spectroscopy (FT-IR). †9-azajulolidine (9-AJ).
NR3
α,β-Unsaturated
acylammonium (3)
Ammonium
enolate (7)
Nuc1
ʹ
alkylation of the corresponding malonates with various haloketones
(Supplementary pages 4–11). As depicted in Table 2, a variety of
keto diesters, diketones and dinitriles (entries 1–5) participate in
the NCMAL process to provide the desired cyclopentanes 14b–f
in 53–83% yields. When a b-keto ester or a-cyano esters was used
as the Michael donor (Table 2, entries 6–8), cyclopentanes 14g–i
were obtained in 55–72% yields with poor diastereoselectivity
(d.r. 1–1.7:1) as expected; however, this is inconsequential given
that these diastereomers would ultimately converge to a single
diastereomer following decarboxylation (vide infra). Introduction
of an a-keto stereocentre, as in ketomalonate 10j, also led to a
mixture of diastereomers 14j (d.r. 2:1) in 84% yield.
R
O
O
–
Cl
– NR3
+
Nuc2
Nuc1
NR3
ʹ
R
E
9
Nuc2
E
8
O
d
ʹ
R
Cl
1
Nuc2
Nuc1
E
NR3
11
O
Variation of the Michael acceptors through the study of a diverse
array of commercially available a,b-unsaturated acid chlorides was
undertaken next. Under optimized NCMAL conditions, cyclopen-
tanes were readily accessed bearing up to three contiguous stereocen-
tres with excellent relative stereochemical control (Table 2, right
column, entries 10–17). b-Substituted acid chlorides uniformly
gave high diastereoselectivity, and the breadth of tolerated b-substitu-
ents was broad, allowing for installation of various functional groups
leading to b-alkyl substituted cyclopentane 14k (entry 10) and ester-
substituted cylopentane 14l (entry 11). Aryl-substituted acid chlor-
ides with various electronic properties (entries 12–14) proceeded in
83–90% yields. Use of sorbic chloride (1g, entry 15) provided a
64% yield of cyclopentane 14p, but allowed for the installation of
an alkene moiety on the cyclopentane, providing a robust functional
handle for subsequent manipulations and diversification. An a-
substituted acid chloride 1h (entry 16) was also reactive under
standard conditions and afforded cyclopentane 14q in 78% yield
bearing two contiguous quaternary stereocentres, one of which is
an all-carbon quaternary centre. Finally, a highly congested cyclo-
pentane 14r was accessible using a,b-dimethyl acryloyl chloride 1i
(entry 17) in 60% yield as a single diastereomer.
O
R
ʹ
R
R
ʹʹ
R
R
β-Lactonization
R
O
Li
–
+
14
10
O
ʹʹ
R
Li
O
O
R
–
NR3
–
Cl
ʹ
ʹ
R
NR3
+
R
Cl
ʹʹ
+
R
R
3
13
Li
Michael
addition
Intramolecular
aldol
H
O
O
R
–
NR3
+
Cl
ʹ
R
ʹʹ
R
R
12
Figure 2 | Generation and reactivity of the chiral unsaturated
acylammonium 3, with contrast to related chiral intermediates 4–6, and a
proposed catalytic cycle leading to bicyclic-b-lactones 14. a, Proposed
synthesis of a,b-unsaturated acylammonium intermediate 3 from acid
chlorides 1 and nucleophilic amines 2. b, Related chiral intermediates include
the acylammonium intermediate 4, ammonium enolate 5 and ammonium
dienolate 6. c, Latent, triple reactivity of the a,b-unsaturated acylammonium
3 first leads to an ammonium enolate 7 following Michael addition. The
latter nucleophilic intermediate leads to a-addition of an electrophile,
delivering acylammonium 8, and final acyl substitution leads to overall
functionalization of three carbons of an a,b-unsaturated acid halide 1.
d, Proposed catalytic cycle employing a latent, triply-reactive species 11, such
as the keto anion 10, possessing two nucleophilic sites and one electrophilic
site, capable of reaction with unsaturated acylammonium 3 to form three
bonds resulting in cyclopentanes 14 bearing a fused b-lactone through a
Michael–aldol-lactonization organocascade process.
Development of an enantioselective NCMAL process. With a view
to applying this complexity-generating process to bioactive natural
product synthesis, we next explored an enantioselective variant of
the NCMAL process. In line with our previous findings20, the
chiral isothiourea homobenzotetramisole (HBTM), developed by
Birman43, was found to be the optimal catalyst to promote an
enantioselective NCMAL (Table 3). Applying the aforementioned
optimized conditions for the racemic NCMAL, HBTM uniformly
delivered cyclopentanes (þ)-14a, (þ)-14c and (þ)-14d in
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1788
ARTICLES
Table 2 | Scope of the racemic NCMAL organocascade process.
O
R1
Cl
R1
R2
EWG
R2
1.0 equiv.
LiHMDS
O
EWG
EWG
1 (1.3 equiv.)
20 mol% 4-PPY (2a)
EtN(iPr)2 (1.0 equiv.)
EWG
THF
O
0
23 o
C
0 o
C
O
CH2Cl2, 0 o
10 min
C
–78
20 min
Me
2–4 min (addition time)
4–24 h
10 (1.0 equiv.)
( )-14
Varying the Michael donor with acryloyl chloride 1a
Entry Michael donor Bicyclic-b-lactone % yield (d.r.)*,†
Varying the Michael acceptor with dimethyl acetonylmalonate 10a
Entry Michael acceptor
Bicyclic-b-lactone % yield (d.r.)*,†
O
R
RO2C
RO2C
H
1
(+)-14b: R ¼ tBu
73 (.19:1)
10
(+)-14k: R ¼ Me
H
O
O
94 (.19:1)‡
RO2C
RO2C
MeO2C
R
Cl
2
3
(+)-14c: R ¼ allyl
11
(+)-14l: R ¼ CO2Et
O
O
MeO2C
1b-c
O
83 (.19:1)
91 (.19:1)
Me
Me
(+)-14d: R ¼ Bn
53 (.19:1)
10b-d
O
p-R-Ph
H
R
H
4
5
(+)-14e: R ¼ C(O)Me
64 (.19:1)
12
13
14
(+)-14m: R ¼ H,
O
O
R
R
90 (.19:1)‡
MeO2C
Cl
R
O
(+)-14f: R ¼ CN
(+)-14n: R ¼ NO2,
O
MeO2C
83 (.19:1)
Me
60 (.19:1)
R
O
Me
(+)-14o: R ¼ OMe
( )-14m-o
10e-f
1d-f
87 (.19:1)
O
Me
64 (.19:1)
15
OMe
OMe
6
7
(+)-14g: R ¼ C(O)Me
72 (1:1)
H
O
O
O
Me
Cl
H
O
(+)-14h: R ¼ CN
MeO2C
O
R
65 (1.7:1)
R
1g
Me
O
O
MeO2C
Me
( )-10g-h
( )-14p
Oallyl
Oallyl
O
Me
8
55 (1.16:1)
16
78 (.19:1)
H
O
O
O
MeO2C
MeO2C
O
Cl
O
O
Me
NC
NC
Me
Me
O
1h
( )-14q
( )-10i
( )-14i
60 (.19:1)‡
Me
H
O
Me
9
MeO2C
MeO2C
84 (2:1)
17
Me
O
MeO2C
MeO2C
O
MeO2C
MeO2C
Me
Cl
O
O
Me
O
Me
( )-14j
Me
Me
1i
( )-10j
( )-14r
*All yields refer to isolated yields. †Diastereomeric ratios were determined by 1H NMR (500 MHz) analysis. ‡Relative stereochemistry verified by X-ray analysis. 4-PPY ¼ 4-(pyrrolidin-1-yl)pyridine.
59–74% yields and 93–98% e.e. (Table 3, entries 1–4). The bis-allyl and 1d,g gave cyclopentanes (þ)-14k,l and (þ)-14m,p in 89–99%
malonate ester 10c was of particular interest for enabling further e.e. as single diastereomers in 60–95% yields (Table 3, entries
functionalization or removal of an electron-withdrawing group 6–12), including those bearing ethyl ester and alkenyl substituents
from the cyclopentane adducts (þ)-14c through mild Pd(0)- suitable for further functionalization. The relative and absolute
catalysed decarboxylative transformations (entry 3)44. The stereochemistry of the alkenyl substituted cyclopentane (þ)-14p
absolute configuration of b-lactone (þ)-14a was confirmed by was confirmed by X-ray analysis (Supplementary Fig. 6). When
X-ray analysis of a derivative following ring opening with b-substituted acid chlorides were studied, an important difference
p-bromobenzylamine (Supplementary Fig. 3). Diketone substrate in reaction outcome was noted under standard conditions.
10e was also well tolerated in the asymmetric process, leading to Optimization studies revealed that extending the addition times of
diketo cyclopentane (þ)-14e in 61% yield and 95% e.e. (Table 3, the acid chloride once again led to high conversions and enantios-
entry 5). The practicality of the NCMAL process was electivities. A competitive, racemic background pathway with the
demonstrated by a gram-scale reaction using dimethyl keto NCMAL, in the case of b-substituted acid chlorides, is proposed
malonate 10a as Michael donor, delivering (þ)-14a with for this difference (Supplementary Table 1). Under these optimized
comparable results (74% yield, 93% e.e., Table 3, entry 2).
conditions, use of (R)-HBTM as catalyst provided the enantiomeric
To probe whether the initial Michael addition could proceed in b-lactones (2)-14l and (2)-14p in 90% yield/89% e.e. and 60%
an enantioselective manner, we next studied b-substituted acid yield/99% e.e., respectively (Table 3, entries 8 and 12). When
chlorides. Indeed, the use of (S)-HBTM with acid chlorides 1b,c applied to sorbic chloride (1g), the bis-allyl keto malonate 10c
4
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1788
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Table3 | Enantioselective NCMAL organocascade.
O
R1
Cl
R1
S
R2
N
1.0 equiv.
EWG
R2
Ph
O
20 mol%
LiHMDS
EWG
EWG
i.
ii.
iii.
(S)-HBTM
THF
1 (1.3 equiv.)
N
EWG
O
EtN(iPr)2 (1.0 equiv.)
0 o
C
0
23 o
C
6–24 h
–78
10 min
O
CH2Cl2, 0 o
10 min
C
Me
(S)-HBTM (2b)
(+)- or (–)-14
10 (1.0 equiv.)
Entry
Michael donor (EWG)
Acid chloride
Bicyclic-b-lactone
% yield (d.r.)*
% e.e.
1†
10a (CO2Me)
10a
10c (CO2allyl)
10d (CO2Bn)
10e (C(O)Me)
(þ)-14a‡ (EWG ¼ CO2Me)
(þ)-14a
72 (.19:1)
74 (.19:1)
74 (.19:1)
59 (.19:1)
61 (.19:1)
97
93
95
98
95
H
O
O
EWG
2†,§
3†
Cl
(þ)-14c (EWG ¼ CO2allyl)
(þ)-14d (EWG ¼ CO2Bn)
(þ)-14e (EWG ¼ C(O)Me)
O
EWG
4†
5†
1a
Me
O
Me
H
6
10a
(þ)-14k
80 (.19:1)
94
O
MeO2C
MeO2C
Cl
O
O
1b
Me
H
O
EtO2C
7†
8†
10a
10a
(þ)-14l
95 (.19:1)
90 (.19:1)
90
89
O
O
MeO2C
(2)-14l**
EtO2C
Cl
MeO2C
1c
Me
H
O
O
Ph
9
10a
10a
(þ)-14m
(þ)-14m
80 (.19:1)
78 (.19:1)
99
90
10}
MeO2C
MeO2C
Cl
O
1d
Me
Me
11
12
13
10a
10a
10c
(þ)-14p‡ (EWG ¼ CO2Me)
(2)-14p**
(þ)-14s (EWG ¼ CO2allyl)
62 (.19:1)
60 (.19:1)
54 (.19:1)
99
99
94
Cl
H
O
EWG
EWG
1g
O
Me
O
Me
O
14
10a
(þ)-14q
80 (.19:1)
99
MeO2C
MeO2C
Cl
O
Me
1h
*All yields refer to isolated yields, enantiomeric excess was determined by chiral GC or high-performance liquid chromatography (Supplementary Figs 1 and 2), diastereomeric ratios were determined by 1H NMR
(500 MHz), and addition of acid chloride was over a 2 h period. Reaction times varied from 6 to 24 h (see Supplementary Information for reaction details). †Acid chlorides were added over 4 min. ‡Absolute
stereochemistry was confirmed by X-ray analysis of (þ)-14p and a derivative of (þ)-14a (see Supplementary Figs 6 and 3, respectively) and others assigned by analogy. §Reaction was performed on gram scale.
}5 mol% (S)-HBTM was employed. **(R)-HBTM was employed as catalyst.
provided cyclopentane (þ)-14s in 54% yield and 94% e.e. as a single combined with acryloyl chloride (1a) to give the tricyclic 5,5,4-
diastereomer. a-Methacryloyl chloride (1h) was also a viable sub- bicyclic system 14t as a single diastereomer in 91% yield (Fig. 3a).
strate, delivering the sterically congested cyclopentane (þ)-14q In contrast, cyclohexanone 10l afforded the corresponding
bearing two contiguous quaternary carbons, one being an all- tricyclic products 14u in 70% yield as a 1:1 mixture of
carbon quaternary centre in 80% yield and 99% e.e. (entry 14). diastereomers, probably due to the lower energy difference
Although we determined that lower catalyst loadings (5 mol%) between
cis-
and
trans-fused
5,6-bicyclic
systems.
were possible in some cases with only slight diminution in yield Cyclohexanedione 10m also participated as a Michael donor with
and enantioselectivity (Table 3, entry 9 versus entry 10), we gener- acryloyl chloride (1a) to give the tricyclic cyclopentane 14v with a
ally utilized 20 mol% catalyst loading to minimize total reaction bridged topology, albeit in 25% yield (Fig. 3b). The relative
times and maximize enantioselectivity.
stereochemistry was confirmed by single-crystal X-ray analysis
(inset, Fig. 3b; Supplementary Fig. 9), and the bridged
Extensions of the NCMAL to polycyclics, in situ activation and cyclopentane in 14v is reminiscent of one substructure of the
aldehydes. To demonstrate the utility of the described gibberellin family of terpenoids (Fig. 1a)45. The tetralone-derived
organocascade process for ring annulation leading to more malonate 10n also participated in the NCMAL; however, the
complex molecular architectures,
a collection of polycyclic presumed intermediate b-lactone 15, which has a benzylic C–O
carbocycles with fused or bridged topology were targeted using bond, underwent facile decarboxylation to deliver cyclopentene
monocyclic Michael donors. Cyclopentanone 10k was readily 16. Following hydrogenation and Krapcho decarboxylation,
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1788
ARTICLES
a
O
H
1a (1.3 equiv.)
20 mol% 2a
O
CO2Me
CO2Me
CO2Me
O
24 h
CO2Me
b
H
O
OMe
1a (1.3 equiv.)
O
H
O
20 mol% 2a
( )-10k
( )-14t: (91%, d.r. >19:1)
O
MeO2C
8 h
O
H
O
O
O
CO2Me
CO2Me
1a (1.3 equiv.)
20 mol% 2a
CO2Me
CO2Me
( )-10m
( )-14v (25%, d.r. >19:1)
O
H
24 h
( )-10l
( )-14u: (70%, d.r. 1:1)
O
c
1) H2, Pd/C, MeOH
2) LiCI, DMSO, H2O,
CO2Me
CO2Me
H
1a (1.3 equiv.)
CO2Me
CO2Me
O
μW
CO2Me
20 mol% 2a
CO2Me
O
H
H
CO2Me
6 h
(54%)
H
( )-16
( )-17(61%, d.r. 1:1)
( )-10n
( )-15
e
EtO2C
EtO2C
H
d
H
O
H
O
O
O
Pd2(dba)3-CHCl3 (9.3 mol%)
PPh3 (4.6 mol%), CH3CN
NC
10o
NC
O
AllylO2C
77
(75%, >19:1 d.r.)
23 oC, 23 h
1.0 equiv.
LiHMDS, THF
–78
10 min
0 o
C
Me
Me
( )-14i (d.r. 1.16:1)
( )-14x
Li
O
EtO2C
EtO2C
EtO2C
OEt
H
H
O
Li
O
18
19
O
TsCl (2.10 equiv.)
LiHMDS (2.05 equiv.)
THF, 23 oC, 30 min
f
20a:R = H
20b:R = Ts
RO
(2.0 equiv.)
1a (1.3 equiv.)
20 mol% 2a
12 h
MeO2C
1.0 equiv.
LiHMDS, THF
H
2a (1.1 equiv.)
O
H
H
CO2Me
O
MeO2C
O
0 o
C
CH2Cl2/THF, 23 o
(20%, d.r. >19:1)
C
EtO2C
EtO2C
–78
10 min
CO2Me
O
O
Me
10a (1.0 equiv.)
( )-14z
( )-14y (60%)
Figure 3 | Rapid molecular complexity generation, structural modifications of cyclopentane products, and extensions of both accessible Michael donors
and unsaturated acylammonium intermediates. All NCMAL reactions were performed under the standard reaction conditions shown in Table 2 unless noted
otherwise. a–c, Monocyclic Michael donors with acryloyl chloride deliver tricyclic 5,5- and 5,6-fused cyclopentyl systems 14t and 14u (a), bridged tricyclic
cyclopentanes (b), truncated steroid intermediates through bis-decarboxylation (c). d, Mild Pd(0)-mediated reductive decarboxylation leads to cyano-
substituted cyclopentane 14x. e, Application of aldehyde-containing Michael donors. f, In situ generation of a tosyl anhydride from unsaturated acids provides
a useful bicyclic ring annulation procedure. Relative stereochemistry of 14t, 14v, 14x was determined by X-ray analysis (Supplementary Figs 8–10). Insets are
single-crystal X-ray structures of 14v and 14x.
monoester 17 was obtained, demonstrating the removal of an bearing an additional stereocentre (Fig. 3d). The relative
activating group in the Michael donor. Furthermore, monoester stereochemistry of 14x was verified by X-ray analysis (inset,
17 resembles a previously described steroidal intermediate46 Fig. 3d; Supplementary Fig. 10). To the best of our knowledge,
(Fig. 1b). A milder method was also sought for removal of one this is the first example of ester decarboxylation in the presence of
of the activating groups required for competent, soft Michael a b-lactone (Fig. 3d).
donors. The Pd(0)-mediated decarboxylation of the allyl ester
Extension of the NCMAL from ketone substrates to the corre-
substituted cyclopentane 14i was explored47. Mild conditions sponding aldehyde malonates was expected to be challenging
were identified that led to reductive decarboxylation of the given the potential for side reactions of the reactive aldehyde
mixture of diastereomeric cyclopentanes 14i at 77 8C, which under the basic conditions of the NCMAL. However, we were
importantly left the b-lactone intact and converged to
a
prompted to develop a NCMAL strategy towards these types of
single diastereomer of the cyano-substituted cyclopentane 14x bicyclic-b-lactones given the structure of vibralactone A (Fig. 1b).
6
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1788
ARTICLES
a
Li
H
O
O
H
Cl
NR3
MeO2C
O
O
Li
O
MeO2C
Me
O
OMe
O
Me
Me
Me
MeO2C
Alleviates
1,3-strain
H
nO
σ*
C-S
MeO2C
MeO
12
A
Me
14
Michael
addition
Aldol-
β-lactonization
(observed product)
MeO2C
MeO2C
Me
Me
Cl
MeO2C
Cl
NR3
Li
H
O
H
MeO2C
H
O
O
Me
Me
ʹ
12
O
ʹ
14
A1,3-strain
1c (1.5 equiv.)
20 mol%
b
O
S
O
O
(–)-BTM (2c)
BnO2C
CO2Bn
N
O
22
EtO2C
BnO
N
EtO2C
Ph
OBn
CH2Cl2
–20 oC, 20 h
LiHMDS, THF
– 78 oC, 30 min
CO2Et
CO2Et
CO2Bn
BnO2C
O
O
(S)-BTM (2c)
Li
(+)-23 (53% yield, >19:1 d.r., 93% e.e.)
( )-21
( )-10p
NHR
OH
4-BrPhCH2NH2
O
EtO2C
THF, 23 oC, 40 h
CO2Et
BnO2C
CO2Bn
(–)-24
(R = 4-bromobenzyl)
Figure 4 | Proposed transition-state arrangements to rationalize the stereochemical outcome of the NCMAL and extension to a multicomponent
cascade process. a, Transition-state arrangement rationalizing facial selectivity with respect to both the Michael donor (enolate) and Michael acceptor
(a,b-unsaturated acylammonium) during the Michael addition, premised on the X-ray structure of the HBTM-unsaturated acylammonium by Smith38
.
The rationale for the diastereoselectivity of the aldol step is premised on minimization of A1,3-strain leading to cyclopentane 14 as the only observed product
following b-lactonization. b, Development of a Michael–Michael–aldol-b-lactonization multicomponent organocascade employing (S)-benzotetramisole
(BTM, 2c), leading to 6,5,4-tricyclic cyclohexane (þ)-23. Subsequent ring opening with p-bromobenzylamine delivered crystalline amide 24 (inset, single-
crystal X-ray structure, phenyl rings omitted for clarity) enabling stereochemical confirmation.
We envisioned that, upon deprotonation of the malonate moiety of Models rationalizing stereoselectivity of the NCMAL. Recently,
aldehyde 10o, equilibrium would be established between the the Smith group reported an X-ray crystal structure of an
lithiated malonate anion 18 and the cyclopropyl lithium alkoxide HBTM-derived, unsaturated acylammonium salt38 that supports a
19 that could mask the reactivity of the aldehyde48. Indeed, metalla- nO ꢀ s*C-S interaction between the acylammonium oxygen and
tion of aldehyde malonate 10o and addition of acryloyl chloride the sulfur atom of the isothiourea first proposed by Birman for
(1a) in the presence of 20 mol% 4-PPY led to the desired cyclopen- these catalysts (Fig. 4a)49. The observed facial selectivity during the
tane 14y in 60% yield (Fig. 3e).
Michael addition results from a combination of the nO ꢀ s*C-S
We also demonstrated that in situ activated carboxylic acids could interaction, the s-trans conformation of the unsaturated
be utilized in the NCMAL, greatly expanding the variety of accessible acylammonium, and the half-chair conformation of the
unsaturated acylammonium intermediates 3. Application of this pyrimidine ring enforced by the planarity of the C–N–C moiety.
in situ activation process to fumaric acid monoethyl ester delivered These factors place the phenyl ring in
a
pseudoaxial
cyclopentane 14l, previously prepared from the acid chloride orientation, effectively blocking the re face of the unsaturated
(Table 2, entry 11), in 69% yield and .19:1 d.r. (in situ activation acylammonium with (S)-HBTM. The high diastereoselectivity
reaction not shown, Supplementary page 44) with 20 mol% 4-PPY. observed during the aldol step derives from the minimization of
In a more challenging setting involving the use of a less reactive A1,3-strain described previously21.
a,b-disubstituted unsaturated acid, commercially available
cyclopentene acid 20a was activated in situ with p-toluenesulfonyl A multicomponent process incorporating the NCMAL. With a
chloride to the corresponding tosyl anhydride 20b and, without view to combining the efficiency of the described organocascade
isolation, slow addition of this intermediate to the anion of keto with a multicomponent reaction50, we sought to perform an initial
malonate 10a afforded the tricyclic 5,5,4-cyclopentyl system 14z in Michael reaction to obtain a competent Michael donor for the
20% yield as a single diastereomer, providing a useful bicyclic ring subsequent Michael–aldol-lactonization to rapidly achieve
annulation process (Fig. 3f).
molecular complexity in a highly atom-economic manner. We
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7
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1788
ARTICLES
The filtrate was then concentrated by rotary evaporation, and the crude mixture
analysed by 1H NMR, which indicated .19:1 d.r. Purification by an automated flash
chromatography system (gradient of EtOAc/hexanes) afforded a single diastereomer
of bicyclic-b-lactone (þ)-14a (0.9497 g, 74%) as a colourless oil. Enantiomeric
excess was determined by chiral gas chromatography analysis in comparison with
authentic racemic material; tminor ¼ 251.6 min, tmajor ¼ 262.6 min, 93% e.e. Spectral
data matched that previously reported20, and absolute stereochemistry was assigned
following b-lactone ring opening with p-bromobenzylamine as described in the
Supplementary Information.
envisioned that in situ generation of the ketomalonate anion 10p
through a Michael addition would initiate the cascade process and
ultimately lead to a cyclohexyl fused-b-lactone 23 (Fig. 4b).
Following extensive optimization, a three-component process was
realized from b-ketoester 21, ethyl fumaroyl chloride (1c) and
dibenzyl 2-methylenemalonate (22) to provide the 6,5,4-tricyclic
cyclohexane (þ)-23 in 53% yield and 93% e.e., generating four
contiguous stereocentres, three new C–C bonds, one C–O bond
and two new rings in a highly stereoselective manner with
(S)-BTM (2c) as nucleophilic promoter. The relative and absolute
configuration was confirmed following ring opening of the
b-lactone with p-bromobenzylamine to afford amide (2)-24
(inset, Supplementary Fig. 11). This three-component reaction
highlights the potential of incorporating a,b-unsaturated
Procedure for multicomponent Michael–Michael–aldol-b-lactonization
delivering cyclohexane (1)-23. An oven-dried, 100 ml round-bottomed flask was
charged with a solution of LiHMDS (1.80 ml of 1.0 M solution in THF, 1.80 mmol,
1.2 equiv.) in THF (2.5 ml) and cooled to 278 8C. Following slow addition of a
solution of cyclopentanone 21 (234 mg, 1.50 mmol, 1.0 equiv.) in THF (2.5 ml), the
reaction mixture was warmed to 220 8C and stirred for 30 min. A solution of diester
21 (1.80 ml of 1.0 M solution in benzene, 1.80 mmol, 1.2 equiv) in THF (2.5 ml) was
added dropwise. After 1 h at 220 8C, a solution of (S)-BTM (75.7 mg, 0.30 mmol,
20 mol%) and EtN(iPr)2 (194 mg, 1.50 mmol, 1.0 equiv.) in CH2Cl2 (2.5 ml) was
added. A solution of acid chloride 1c (366 mg, 2.25 mmol, 1.5 equiv.) in CH2Cl2
(5.0 ml) was then added at 220 8C over 5 h by a syringe pump. The reaction
temperature was maintained at 220 8C throughout the addition of 1c, and the
reaction was stirred at this temperature for 15 h. Upon completion (as judged by thin
layer chromatography), the reaction was concentrated by rotary evaporation and the
product was purified by an automated flash chromatography system (gradient of
EtOAc/hexanes) to afford a single diastereomer of tricyclic-b-lactone (þ)-23
(457 mg, 53% yield) as a yellow, viscous liquid. Complete characterization data is
provided in the Supplementary Information. The relative and absolute
acylammonium intermediate
3
into the design of
multicomponent, organocascade processes.
The complexity-generating, NCMAL process described herein
delivers high synthetic efficiency for complex cyclopentane synthesis
by the formation of three new bonds, up to three stereogenic centres
and two rings, in a single operation, from simple starting materials.
Furthermore, the simple yet powerful asymmetric activation mode
of commercially available, unsaturated acid chlorides, utilized to its
full potential for the first time by reaction at all three positions, pro-
vides a new paradigm for the design of additional organocascade pro- stereochemistry was confirmed by X-ray analysis (Supplementary Fig. 11) following
b-lactone ring opening with p-bromobenzylamine.
cesses. This tandem reaction was rendered highly enantioselective
with the application of chiral isothiourea catalysts. Extensions to poly-
cyclic carbon frameworks and multicomponent processes such as
Michael–Michael–aldol-lactonization demonstrate the potential of
Received 6 June 2013; accepted 26 September 2013;
published online 3 November 2013
this concept for more sophisticated reaction designs aimed at the syn-
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250 ml round-bottomed flask equipped with a magnetic stir bar was added
dimethyl 2-(2-oxopropyl) malonate (10a, 1.0 g, 5.32 mmol, 1.0 equiv.) together with
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Acknowledgements
This work was supported by the National Science Foundation (CHE- 1112397) and the
Robert A. Welch Foundation (A-1280), together with partial support from the National
Institutes of Health (GM 069874). The authors thank N. Harvey for synthesis of HBTM and
assistance with early studies of the NCMAL. N. Bhuvanesh (Center for X-ray Analysis,
TAMU) and W. K. Russell (Laboratory for Biological Mass Spectrometry, TAMU) secured
X-ray crystal structure and mass data, respectively.
Author contributions
G.L. initiated the studies of the a,b-unsaturated acylammonium intermediate from acid
chlorides. D.R., G.L. and M.E.S. were involved in the design of experiments for exploration
of the NCMAL. D.R. and K.N.V. conceived and developed the three-component NCMAL
process. G.L., M.E.S., K.N.V. and R.L.M. performed the experiments. D.R., G.L. and
M.E.S. composed the manuscript with input from all authors.
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cycloaddition of zwitterionic dienolates generated from a,b-unsaturated acid
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asymmetric annulation processes. Chem. Sci. 4, 2193–2200 (2013).
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Additional information
Supplementary information and chemical compound information are available in the
online version of the paper. Reprints and permissions information is available online at
www.nature.com/reprints. Correspondence and requests for materials should be
addressed to D.R.
Competing financial interests
The authors declare no competing financial interests.
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