A catalytic asymmetric three-component 1,4-addition/aldol reaction: Enantioselective synthesis of the spirocyclic system of vannusal A

Article abstract of DOI:10.1002/anie.200500789

(Chemical Equation Presented) Three's not always a crowd: A three-component reaction involving α,β-unsaturated enones 1, aldehydes 2, and alkenyl zirconium species 3 in the presence of a Rh-binap catalyst leads, sequentially, to aldols 4, enones 5, and 2,

Full text of DOI:10.1002/anie.200500789

Communications
Multicomponent Reactions
A Catalytic Asymmetric Three-Component
1,4-Addition/Aldol Reaction: Enantioselective
Synthesis of the Spirocyclic System of
Vannusal A**
K. C. Nicolaou,* Wenjun Tang, Philippe Dagneau, and
Raffaella Faraoni
The advantages of multicomponent reactions over the more
common two-component processes have been widely dem-
onstrated and reviewed.[1] Efficient asymmetric versions of
such reactions offer even greater benefits to the art of
chemical synthesis, as these can provide expedient access to
polyfunctionalized molecules in enantioenriched form, start-
ing from simple prochiral building blocks.[2,3] During a
program directed towards the total synthesis of vannusal A
(1, Scheme 1), an architecturally complex marine natural
product isolated from the ciliate Euplotes vannus,[4] the key
optically enriched spirocyclic intermediate 2 was required.
This demand led us to the development of an asymmetric
multicomponent reaction that combined a,b-unsaturated
[*] Prof. Dr. K. C. Nicolaou, Dr. W. Tang, P. Dagneau, Dr. R. Faraoni
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax: (+1)858–784–2469
E-mail: kcn@scripps.edu
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
[**] We thank Dr. D. H. Huang and Dr. G. Siuzdak for NMR
spectroscopic and mass spectrometric assistance, respectively.
Financial support for this work was provided by grants from the
National Institutes of Health (USA) and the Skaggs Institute for
Chemical Biology, and a fellowship from the Swiss National Science
Foundation (to R.F.).
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DOI: 10.1002/anie.200500789
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process capable of delivering enantiomerically enriched
products as reported herein. According to our plan, a chiral
rhodium complex was to act as a catalyst to induce the
asymmetric 1,4-addition of zirconium species III to a,b-
unsaturated ketone I. This should, in turn, furnish a rhodium
enolate intermediate, whose trapping with aldehyde II was
expected to lead first to aldol IV and thence to enone V and
disubstituted cyclic ketones VI (by sequential elimination of
water and reduction, respectively). It was, therefore, hoped
that the products from this multicomponent reaction would
include any one or more desired compounds IV to VI
(Scheme 2).
This work was initiated with some considerable success, as
demonstrated in Scheme 3 in the case of a,b-unsaturated
Scheme 1. Stucture of vannusal A (1) and retrosynthetic analysis of
spirocyclic building block 2.
enones, aldehydes, and alkenyl zirconium species in the
presence of a chiral rhodium catalyst to give enantioselective
access to 2,3-disubstituted cycloalkanones. Herein we report
this new synthetic technology and describe its application to
the construction of enantioenriched building block 2, which
represents the spiro domain of vannusal A (1).
Scheme 2 shows the general strategy for the intended
three-component (I, II, and III) catalytic asymmetric con-
Scheme 3. Proof of principle of the catalytic asymmetric three-compo-
nent reaction. Reagents and conditions: a) [Cp2Zr(H)Cl], THF, 30 min;
b) 7 (1.2 equiv), 8 (1.2 equiv), 9 (1.0 equiv), [Rh(cod)(MeCN)2]BF4
(0.05 equiv), (S)-binap (0.06 equiv), THF, 258C, 12 h, 50% (10; ꢀ4:1
isomeric ratio); c) MsCl (3.0 equiv), Et3N (6.0 equiv), 0!258C,
30 min; then Al2O3 (excess), 12 h, 95% (11, E:Zꢀ20:1, 98% ee);
d) PhSiH3 (1.5 equiv), [(Ph3P)CuH]6 (1 mol%), toluene, 258C, 6 h,
85% (trans/cisꢀ1:3). cod=cyclooctadiene, (S)-binap=(S)-(ꢁ)-2,2’-
bis(diphenylphosphino)-1,1’-binaphthyl, Ms=methanesulfonyl.
cycloheptenone (7). Thus, mixing of 7 with the zirconium
species 8 (derived from 1-octyne and [Cp2Zr(H)Cl])[7] and
[5]
aldehyde 9 in the presence of [Rh(cod)(MeCN)2]BF4 and
(S)-binap as the catalyst system in THFat 258C for 12 h led to
the formation of 10 as a mixture of two diastereoisomers
( ꢀ 4:1, 50% combined yield). This mixture was subjected to a
standard mesylation/elimination sequence to produce enone
11 (E/Z ꢀ 20:1; Table 2) in 95% overall yield. Furthermore,
and gratifyingly, the enantiopurity of this enone ([a]3D3 =
+ 118.5 (CHCl3, c = 1.0)) was found to be 98% ee by chiral
HPLC (Chiralcel, OD-H). Finally, this enone 11 was reduced
with PhSiH3 in the presence of a catalytic amount of
Scheme 2. General scheme for the catalytic asymmetric three-compo-
nent reaction (I + II + III!IV!V!VI).
struction of aldol-type compounds IV, a,b-unsaturated
enones of type V, and 2,3-disubstituted cyclic ketones of
type VI. This proposed multicomponent reaction was parti-
ally based on the pioneering work of Oi, Sato, and Inoue,[5]
who demonstrated the efficient rhodium-catalyzed addition
of alkenyl zirconium species to enones (under non-aqueous
conditions) to afford 1,4-adducts. Furthermore, the elegant
studies of the Hayashi group[6] on the catalytic cycle of the
rhodium-catalyzed conjugate addition of B-aryl-9-BBN to a
reactive vinyl ketone, which showed that a transient rhodium
enolate can react with electrophiles, were key to this proposal.
Both studies, however, stopped short of a three-component
[8]
[(Ph3P)CuH]6 (1 mol%) to afford 2,3-disubstituted cyclo-
heptanones 12 (trans/cis ꢀ 1:3; 85% combined yield).
With regards to a mechanism for this process, we envisage
a similar catalytic cycle (see Scheme 4) to those previously
proposed by the Oi and Inoue group[5] and the Hayashi
group[6] to explain their enantioselective 1,4-addition of
zirconium species, aryl boronic acids, or B-aryl-9-BBN
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good yields (30–62%) through the three-component 1,4-
addition/aldol reaction. Good to excellent enantioselectivities
(78–98% ee) were observed for the corresponding enones V.
Various aliphatic aldehydes that carry linear or branched
chains or ring systems at their a sites were employed
successfully. It is noteworthy that benzaldehyde and trimethyl
acetaldehyde did not prove to be suitable substrates for these
reactions. The alkenyl zirconium species employed in these
asymmetric processes were derived from terminal alkynes
with different aliphatic or functionalized carbon chains.
The developed technology was successfully applied to the
synthesis of the spiro system 2 of vannusal A (1), as depicted
in Scheme 5. Thus, enone 4, alkenyl zirconium species 8
(generated in situ from 1-octyne and [Cp2Zr(H)Cl])[7] and
aldehyde 13 were combined in the presence of [Rh(cod)-
(MeCN)2]BF4 (5 mol%) and (S)-binap (6 mol%) in THF at
Scheme 4. Proposed mechanism for the asymmetric three-component,
rhodium-catalyzed 1,4-addition/aldol reaction (I + II + III!IV).
L=CH3CN, cod (cycloocta-1,5-diene), or thf.
reagents to a,b-unsaturated enones. Thus, transmetalation of
the alkenyl zirconium species III may lead to the rhodium
alkenyl complex III’’, which could react with cyclic enone I to
form the p-coordination complex I’. Rearrangement of I’,
upon transfer of the alkenyl group onto the 4-position of the
enone, should lead to the rhodium enolate I’’. This chiral
enolate may then engage the aldehyde II in an aldol reaction,
generating rhodium complex IV’ through a six-membered-
ring transition state [I’’ + II]°. Transmetalation of IV’ with
another alkenyl zirconium species III could then lead to
zirconium alkoxide IV’’ and regeneration of rhodium alkenyl
complex III’’. Hydrolysis of IV’’ provides aldol product IV.
Both the chemoselectivity of the rhodium alkenyl species III’’
in differentiating between the conjugated ketone I and an
aldehyde II, as well as the ability of the postulated transient
rhodium enolate to engage the aldehyde component in an
aldol reaction,[9,10] are crucial for the success of this process.
Next, we examined the generality and scope of the present
enantioselective reaction. As demonstrated in Table 1, this
process proceeded well with five- (Table 1, entries 7 and 8),
six- (Table 1, entries 1–6), and seven-membered cyclic enones
(Table 1, entries 9–11), as well as an acyclic ketone (Table 1,
entry 12). Thus, a series of aldol products IV were obtained in
Scheme 5. Construction of spirocyclic building block 2 of vannusal A.
Reagents and conditions: a) [Rh(cod)(MeCN)2]BF4 (5 mol%), (S)-
binap (6 mol%), THF, 258C, 12 h, 52%; b) MsCl (2.0 equiv), Et3N
(3.0 equiv), CH2Cl2, 258C, 30 min; c) DBU (2.0 equiv), THF, 258C, 2 h,
(15, E:Zꢀ13:1), 85% (over two steps); d) PhSiH3 (1.5 equiv),
[(Ph3P)CuH]6 (1 mol%), toluene, 258C, 6 h, (trans/cisꢀ2:1); e) aque-
ous HF (48%;10 equiv), THF, 258C, 2 h, 79% (over two steps); f) PCC
(1.5 equiv), CH2Cl2, 258C, 2 h, 91%; g) MeOH, NH4Cl (0.01 equiv),
reflux, 2 h, 98%; h) TMSI (1.5 equiv), Et3N (1.2 equiv), CH2Cl2, 0 to
258C, 2 h, 50%; i) KH (5.0 equiv), (MeO)2CO (10 equiv), THF, reflux,
2 h; j) Mn(OAc)3 (2.5 equiv), Cu(OAc)2 (1.2 equiv), EtOH, reflux,
2 h, 68% (over two steps), (2, 96% ee). DBU=1,8-diazabicyclo-
[5.4.0]undec-7-ene, PCC=pyridinium chlorochromate, TMS=trimethyl-
silyl.
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Table 1: Catalytic asymmetric three-component 1,4-addition/aldol reaction of enones I, aldehydes II, and alkenyl zirconium species III: preparation of
enantiomerically enriched 2,3-disubstituted aldols IV and enones V.[a]
Entry
I
II
III’
IV
Yield [%][b] Ratio[c]
V[d]
Yield [%][e] ee [%][f] [a]D
1
53
52
51
41
30
2:1
1.4:1
4:1
85
96
96
96
95
94
+
+
+
+
+
2
3
4
5
85
89[g]
83[h]
88
5.9:1
1.1:1
6
7
8
9
58
55
62
50
1:1
1:1
80
91
94
80
96
78
79
98
+
+
+
+
5.3:1
1.3:1
10
11
34
61
3.1:1
3.7:1
90
82
93
94
+
+
12
48
mixture[i]
85
85
+
[a] Reactions were carried out at ambient temperature on a 1.0-mmol scale (aldehyde) in THF in the presence of catalytic amounts of [Rh(cod)(MeCN)2]BF4 and
(S)-binap (see Experimental Section for more details). [b] Yields of isolated products. [c] Ratios were determined by 1H NMR spectroscopy. The relative
configurations were not determined. [d] The E enones were predominantly formed along with small amounts of the Z enones (E/Z>9:1), unless otherwise
specified. The absolute configurations of products in entries 1–11 were tentatively assigned by analogy with their corresponding 1,4-addition products.[5].
[e] Overall yield of mesylation–elimination (IV!V). [f] The ee values of the E enones were determined by chiral HPLC (chiralpak AD or chiralcel OD-H columns).
1
[g] E/Zꢀ3:1. [h] E/Zꢀ5:1. [i] Four isomers by H NMR spectroscopy.
258C. After 12 h of stirring, aldol product 14 was obtained
(52% yield, ꢀ 1.4:1 ratio of diastereomers). Mesylation of
this mixture, followed by exposure of the resulting products to
DBU, furnished enone 15 (E/Z ꢀ 13:1; Table 2) in 85%
overall yield. The conjugated double bond within 15 was
selectively reduced with PhSiH3 in the presence of a catalytic
the sequence established previously on a similar, racemic,
substrate.[11] Thus, oxidation of hydroxyketone 16 with PCC,
followed by acetalization of the resulting aldehyde, led to 17
(90% yield). Treatment of this acetal 17 with TMSI in the
presence of Et3N gave methoxy spiroketone 18 (48% yield of
the desired diastereoisomer; Table 2). Finally, carboxymethy-
lation of the latter compound 18, followed by exposure to the
radical oxidation conditions of Mn(OAc)3–Cu(OAc)2,
afforded the desired vannusal A key building block 2 (68%;
[8]
amount of [(Ph3P)CuH]6 (1 mol%) which led, after desily-
lation, to disubstituted cyclohexanones 16 (trans/cis ꢀ 2:1,
79% combined yield). From this point, the synthesis followed
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Table 2). Intermediate 2 ([a]3D3 = ꢁ1.0 (CHCl3, c = 1.0)) was
Table 2: Selected physical properties for compounds 2, 11, 15, and 18.
2: Rf =0.43 (silica gel, EtOAc/hexanes 1:5); [a]3D3 =ꢁ1.0 (c=1.0, CHCl3);
thus obtained with 96% ee, as determined by chiral HPLC
(Chiralcel OD-H).
1
IR (film): n˜max =1731 cmꢁ1; H NMR (600 MHz, CDCl3): d=5.61 (dt,
J=15.0, 7.2 Hz, 1H), 5.36 (dd, J=15.0, 7.2 Hz, 1H), 3.68 (s, 3H), 3.54
(dd, J=6.6, 3.0 Hz, 1H), 3.26 (s, 3H), 2.85 (d, J=7.2 Hz, 1H), 2.13–1.80
(m, 9H), 1.73 (m, 1H), 1.57 (m, 1H), 1.45 (m, 1H), 1.33–1.17 (m, 7H),
0.86 ppm (t, J=7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3): d=212.1,
171.4, 136.0, 124.5, 87.6, 69.4, 62.6, 58.3, 53.3, 52.7, 52.1, 36.8, 33.6,
32.1, 32.0, 29.8, 24.4, 23.3, 22.7, 22.4, 14.9 ppm; HRMS (ESI-TOF) (m/z):
calcd for C21H33O4+ [M+H]+: 349.2373; found: 349.2357
The methodology presented herein represents a conven-
ient entry into multifunctionalized and relatively complex
building blocks, starting from comparatively simple and
readily available starting materials. Its scope incorporates
substituted acyclic as well as cyclic ketones. Good to excellent
enantiomeric excess was attained in all cases studied.
Application of this catalytic asymmetric three-component
reaction to the construction of the spirocyclic domain of
vannusal A powerfully demonstrates the applicability and
versatility of this process. The total synthesis of this challeng-
ing triterpene 1 is well underway in our laboratories.
11: Rf =0.46 (silica gel, EtOAc/hexanes 1:5); [a]3D3 =+118.5 (c=1.0,
CHCl3); IR (film) n˜max =2957, 2929, 2855, 1684, 1611, 1458, 1326, 1286,
1
1208, 1122, 974, 938 cmꢁ1; H NMR (400 MHz, CDCl3): d=6.52 (t,
J=7.6 Hz, 1H), 5.51 (dd, J=15.7, 4.0 Hz, 1H), 5.30 (m, 1H), 3.60 (m,
1H), 2.59 (dt, J=13.5, 2.0 Hz, 1H), 2.46 (m, 1H), 2.11–1.97 (m, 5H),
1.88–1.79 (m, 1H), 1.78–1.70 (m, 2H), 1.59–1.50 (m, 1H), 1.49–1.20
(m, 11H), 0.92 (t, J=7.4 Hz, 3H), 0.87 ppm (t, J=6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=216.2, 143.0, 140.0, 131.6, 130.7, 43.4,
37.8, 34.2, 32.7, 31.7, 30.0, 29.4, 28.8, 25.8, 25.1, 22.6, 22.1, 14.1,
14.0 ppm; HRMS (ESI TOF) (m/z): calcd for C19H33O+ [M+H]+:
277.2526; found: 277.2531
Experimental Section
General procedure: The alkyne (1.25 mmol, 1.25 equiv) was added to
[Cp2Zr(H)Cl][12] (1.2 mmol; 1.2 equiv) in anhydrous THF (4 mL)
under argon. The mixture was stirred at 258C for 30 min until it
became homogeneous. In a separate flask, [Rh(cod)(MeCN)2]BF4
(0.05 mmol, 0.05 equiv) and (S)-binap (0.06 mmol, 0.06 equiv) were
dissolved in anhydrous THF (4 mL) under argon and stirred at 258C
for 30 min. The enone (1.2 mmol, 1.2 equiv) was then added to the
resulting red catalyst solution, followed by the aldehyde (1.0 mmol;
1.0 equiv). The zirconium reagent was transferred to this solution
through a cannula, and the resulting mixture was stirred at 258C for
12 h. The mixture was concentrated under reduced pressure, and the
residue taken up in diethyl ether and directly filtered through a small
pad of celite and then concentrated. The resultant crude mixture was
purified by flash column chromatography (silica gel), with Et2O/
hexanes mixtures as eluant, to provide aldol products IV as colorless
oils. Triethylamine (1.8 mmol, 6.0 equiv) and methanesulfonyl chlo-
ride (0.9 mmol, 3.0 equiv) were added to a stirred solution of the aldol
product IV (0.3 mmol) in CH2Cl2 (4 mL) at 08C. The resulting
mixture was allowed to warm to 258C within 30 min, and then basic
alumina (2 g) was added (alternatively, DBU/THF could be
employed for the elimination step). The mixture was then stirred
vigorously at 258C for 12 h, filtered, and concentrated. The residue
was purified by flash column chromatography (silica gel) with EtOAc/
hexanes mixtures as eluant to provide enone product V.
15: Rf =0.41 (silica gel, EtOAc/hexanes 1:5); [a]3D3 =+73.5 (c=1.0,
CHCl3); IR (film) n˜max =2928, 2856, 1688, 1616, 1471, 1463, 1256, 1102,
970, 837, 776 cmꢁ1; 1H NMR (500 MHz, CDCl3): d=6.64 (t, J=7.5 Hz,
1H), 5.34 (dd, J=15.4, 4.8 Hz, 1H), 5.23 (m, 1H), 3.60 (m, 3H), 2.48 (d,
J=17.6 Hz, 1H), 2.23 (m, 2H), 2.08 (m, 1H), 1.96 (m, 2H), 1.91–1.78
(m, 3H), 1.78–1.71 (m, 1H), 1.68–1.56 (m, 2H), 1.32–1.20 (m, 8H), 0.88
(m, 12H), 0.03 ppm (s, 6H); 13C NMR (125 MHz, CDCl3): d=201.8,
140.2, 138.5, 131.9, 131.3, 62.4, 40.2, 38.6, 32.5, 31.7, 31.6, 29.8, 29.4,
28.8, 25.9, 24.1, 22.6, 19.0, 14.0, ꢁ5.3 ppm; HRMS (ESI-TOF) (m/z):
calcd for C24H45O2Si+ [M+H]+: 393.3183; found: 393.3184
18: Rf =0.38 (silica gel, EtOAc/hexanes 1:10); [a]3D3 =+44.6 (c=1.0,
1
CHCl3); IR (film): n˜ =1710 cmꢁ1; H NMR (400 MHz, CDCl3): d=5.37
(dt, J=14.8, 6.8 Hz, 1H), 5.21 (ddt, J=14.8, 9.6, 1.2 Hz, 1H), 3.92 (dd,
J=4.8, 2.4 Hz, 1H), 3.21 (s, 3H), 2.49 (m, 1H), 2.38–2.30 (m, 2H),
2.25–2.10 (m, 2H), 1.96–1.56 (m, 8H), 1.45 (m, 1H), 1.37–1.18 (m, 9H),
0.85 ppm (t, J=6.8 Hz, 3H); 13C NMR (150 MHz, CDCl3): d=212.8,
133.9, 129.7, 88.3, 65.3, 57.4, 48.7, 42.1, 33.3, 32.5, 30.2, 30.0, 29.9, 29.6,
29.6, 23.6, 23.5, 21.6, 14.9 ppm; HRMS (ESI-TOF) (m/z): calcd for
C19H33O2+ [M+H]+: 293.2471; found: 293.2475
Received: March 3, 2005
Published online: May 18, 2005
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Keywords: aldol reaction · asymmetric catalysis ·
.
multicomponent reactions · natural products ·
nucleophilic addition
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[10] Another aldol reaction pathway, involving transmetalation of
the rhodium enolate I’’ with the alkenyl zirconium species III to
generate the zirconium enolate, followed by the engagement of
an aldehyde II for the subsequent aldol reaction, cannot be
excluded at this time in this three-component reaction.
[11] K. C. Nicolaou, M. P. Jennings, P. Dagneau, Chem. Commun.
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[12] [Cp2Zr(H)Cl] was purchased from Strem Chemicals, Inc.
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