Heterocyclic spiranes and dispiranes via enantioselective phosphine-catalyzed [3+2] annulations

Article abstract of DOI:10.1002/adsc.201100748

The synthesis of highly functionalized heterocyclic spiranes has been carried out by [3+2] cyclizations between allenoates and enones, under phosphine catalysis. Excellent enantioselectivity levels (ees up to 99%) have been attained in FerroPHANE-promoted

Full text of DOI:10.1002/adsc.201100748

FULL PAPERS
DOI: 10.1002/adsc.201100748
Heterocyclic Spiranes and Dispiranes via Enantioselective
Phosphine-Catalyzed [3+2]Annulations
Deepti Duvvuru,a Nathalie Pinto,a Catherine Gomez,a Jean-FranÅois Betzer,a
Pascal Retailleau,a Arnaud Voituriez,a,* and Angela Marinettia,*
a
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Centre de Recherche de Gif, 1 av. de la Terrasse, 91198
Gif-sur-Yvette, France
Fax : (+33)-1-6907-7247; e-mail: arnaud.voituriez@icsn.cnrs-gif.fr or angela.marinetti@icsn.cnrs-gif.fr
Received: September 27, 2011; Published online: February 9, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100748.
Abstract: The synthesis of highly functionalized tures. The corresponding sulfoxides have been ob-
heterocyclic spiranes has been carried out by [3+2] tained then via a subsequent, highly diastereoselec-
cyclizations between allenoates and enones, under tive oxidation of the prostereogenic sulfur centre.
phosphine catalysis. Excellent enantioselectivity
levels (ees up to 99%) have been attained in Ferro-
PHANE-promoted cyclizations of this class, leading Keywords:
ACHTUNGTRENUN[NG 3+2]cyclization; enantioselective orga-
to chiral sulfides with unprecedented spiranic struc- nocatalysis; phosphines; spiro compounds; sulfoxides
Introduction
tions are expected to afford spiroheterocycles with
unprecedented molecular scaffolds.
The [3 +2]cyclization between olefins and electron-
The potential usefulness of the targeted heterocy-
deficient allenes or alkynes, usually referred to as the cles can be anticipated, based on the well-established
Lu reaction, has become a benchmark reaction in the importance of analogous compounds in either medici-
field of phosphine organocatalysis.[1] A variety of reac- nal chemistry or enantioselective synthesis. For in-
tion partners has been considered for synthetic pur- stance, piperidinones 1 themselves[9] and some spiro-
poses[2] and enantioselective variants have been also cyclic derivatives thereof[10] are known to display cyto-
developed,[3,4] following on from the pioneering stud- toxic or antimycobacterial activities, while cyclic
ies reported by Zhang in 1997.[5] Noteworthy, these amines,[11] sulfides and sulfoxides[12] afford countless
enantioselective [3+2]cyclizations represent highly chiral auxiliaries for both stoichiometric syntheses
efficient tools to access spirocyclic derivatives with and organic or organometallic catalysis.
quaternary, all-carbon stereogenic centres. Such chal-
lenging synthetic targets can be attained easily, in
mild conditions, with high levels of stereoselectivi- Results and Discussion
ty.[2i,4b,6] The method has been applied notably to the
facile, stereoselective creation of spirocyclopentene In this work, we have investigated the phosphine-cat-
oxindole moieties.[7] Also, phosphine-promoted [3+ alyzed [3+2]cyclizations between ethyl 2,3-butadie-
2]cyclizations on cyclic bis-arylidene ketones afforded noate and the heterocyclic bis-arylidene ketones 1–4
unique spiranic scaffolds with good stereocontrol of as a suitable synthetic approach to spiranic heterocy-
up to five stereogenic centres.[4b,8]
cles. The bis-arylidene ketones 1–3a (Scheme 1) have
As a further step towards molecular complexity, we been prepared by two subsequent aldol condensations
consider here the use of heterocyclic a,b-unsaturated on the corresponding unsubstituted cyclic ketones, ac-
ketones, such as 3,5-bis(arylidene)-4-piperidones 1, di- cording to known procedures.[13] The thiopyran-4-one
hydropyranones 2, dihydrothiopyranones 3, and dihy- 3a was then converted into the corresponding sulfox-
drothiopyranone oxides 4, as substrates in [3+2]cycli- ide 4 by oxidation with NaIO4.[13a] The four substrates
zation processes. The enantioselective [3+2]cycliza- 1–4 were reacted with ethyl butadienoate 5 in the
408
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Adv. Synth. Catal. 2012, 354, 408 – 414

Heterocyclic Spiranes and Dispiranes via Enantioselective Phosphine-Catalyzed [3+2]Annulations
Table 1. Triphenylphosphine-promoted [3+2]annulations on
arylidene thiopyranones.
Entry Substrate Ar
Product Yield [%][a]
Scheme 1. Triphenylphosphine promoted [3+2]cyclizations
on heterocyclic bis-arylidene ketones.
1
2
3
4
5
6
7
3b
3c
3d
3e
3f
3g
3h
2-naphthyl
9-phenanthryl 8c
4-MeOC6H4
4-NO2C6H4
4-ClC6H4
4-MeC6H4
thiophen-2-yl
8b
77
98
8d
8e
8f
8g
8h
75[b]
78[c]
66
presence of a 10 mol% amount of PPh3 as the nucleo-
philic catalyst.
The desired cyclizations took place at room temper-
ature and afforded the spirocyclic derivatives 6–8a in
moderate to good yields. Only minor amounts of side
products are observed in the crude reaction mixtures.
The isolated products are the so-called g-adducts.
They formally result from Michael additions of the al-
lenoate 5, via its g-carbon, to the enone function of
the electrophilic partners. The outcome of these reac-
70
67
[a]
General conditions: 3:5 ratio=1:2, room temperature,
16 h.
[b]
[c]
In refluxing toluene.
1:1 substrate ratios.
tions is therefore fully consistent with the previously Therefore, we next investigated asymmetric variants
observed g-regioselectivity[2n,4b,8a] of most reactions in- of these annulations and our results are shown in
volving non-substituted allenoates and b-substituted Table 2. Thiopyranone 3a was selected as a represen-
a,b-unsaturated ketones, under phosphine catalysis.[14] tative substrate for preliminary studies. It was reacted
Sulfoxide 4 displayed a more complex behaviour. with ethyl allenoate in the presence of several chiral
The prochiral substrate 4 was converted into a mix- phosphorus catalysts, including PhanePhos, DIOP,
ture of cyclization products, which include the two Me-DuPhos, Binap, Binepines and FerroPHANE.[15]
diastereomeric g-adducts with opposite configurations Among these phosphorus derivatives, the two cata-
of the stereogenic sulfur function, as well as small lysts previously identified as the best ones in [3+
amounts of the corresponding a-adducts. Due to its 2]cyclizations, namely t-Bu-Binepine I,[4b] and Ferro-
low selectivity, the [3+2]cyclization on sulfoxide 4 PHANE II, recently developed in our group,[4c] also
cannot be considered so far as a synthetically useful proved the best ones in these reactions. (S)-t-Bu-Bine-
method, while the cyclization on the corresponding pine afforded 8a in 66% yield, 89% ee while (S,S)-
sulfide 3a proved to be a fully convenient, selective FerroPHANE gave an 84% yield and a 92% ee in the
approach to spiranic derivatives. Therefore, after the same reaction (entries 1 and 2 in Table 2). We assume
preliminary experiments in Scheme 1, cyclic sulfides that the final spirocycle 8a obtained in (S,S)-Ferro-
have been selected as preferred substrates for more PHANE-catalyzed cyclizations has a (4S,5R)-configu-
extended studies.
ration, based on the known stereochemical outcome
The cyclization reactions have been extended to of analogous annulations on both acyclic enones[8a]
thiopyranones with various arylidene moieties and arylidene-oxindoles.[7a]
(Table 1): with triphenylphosphine as catalyst, the cor-
More extended experiments have been conducted
responding spirocyclic derivatives 8b–h have been ob- then with FerroPHANE as the catalyst, showing that
tained as single regioisomers in good yields, after op- high levels of enantioselectivity can be attained in
timization of the reaction conditions. The cyclization these cyclizations starting from thiopyranones 3 with
reactions usually proceed at room temperature, by various aryl substituents on the vinyl functions (93–
combining the enones 3 and ethyl butadienoate 5 in a 99% ee, entries 3–9 in Table 2). Also, cyclization on
1:2 ratio, in the presence of a 10 mol% amount of piperidinone 1 could be performed in analogous con-
PPh3. The reaction of 3d has been run in refluxing tol- ditions to afford the corresponding spirocyclic amine
uene to attain good conversion rates, since the elec- 6 in 86% enantiomeric excess (entry 10).
tron-rich aryl group decreases the reactivity of the
double bond.
From the results in Table 2, it appears that cycliza-
tion on the p-nitrophenyl-substituted thiopyranone 3e
As mentioned above, it is well known, from litera- takes place with an especially high enantioselectivity
ture data as well as from our own work, that suitable level, leading to 8e in >99% ee. The excellent enan-
chiral phosphines are able to induce high enantiose- tioselectivity of these reactions, as well as the poten-
lectivity in analogous [3+2]cyclizations on enones. tial usefulness of enantiomerically pure, C2-symmetri-
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Table 2. Enantioselective [3+2]cyclizations promoted by (S)-t-Bu-Binepine I, and (S,S)-FerroPHANE II.
Entry
Substrate
X
Ar
Product
PR3
Yield [%][a]
ee [%]
1
2
3
4
5
6
7
8
9
3a
3a
3b
3c
3d
3e
3f
3g
3h
1
S
S
S
S
S
S
S
S
Ph
Ph
8a
8a
8b
8c
8d
8e
8f
8g
8h
6
I
66
84
86
89
92
94
95
93
>99
93
95
97
86
II
II
II
II
II
II
II
II
II
2-naphthyl
9-phenanthryl
4-MeOC6H4
4-NO2C6H4
4-ClC6H4
4-MeC6H4
thiophen-2-yl
Ph
90
84[b]
65[c]
65
75
S
80[d]
70[e]
10
NMe
[a]
Conditions: 3:5 ratio=1:2, toluene, 408C, 24 h.
In refluxing toluene.
3e:5 ratio=1:1.
At room temperature.
1:5 ratio=1:1, 808C.
[b]
[c]
[d]
[e]
cal sulfides,[12b–d] led us to envision a further extension was thus attempted in the presence of an excess allen-
of the method to the synthesis of analogous C2 sym- oate (Scheme 2). With (S,S)-FerroPHANE as the cat-
AHCTUNGTRENNUNG
metrical sulfides by a double annulation process. Our alyst, the desired dispiranic derivative 10 could be ob-
previous work on [3+2]cyclizations demonstrated tained in 65% yield and >99% enantiomeric excess,
that double annulation processes can take place on according to HPLC analysis. It represents the first ex-
acyclic bis-enones with good diastereo- and enantio- ample of C2-symmetrical bis-spirocyclic derivatives of
control,[8a] however, the double annulations on cyclic this class.[16]
substrates had never been reported before. They are
According to our experiments, this double cycliza-
expected to be somewhat more challenging since they tion process requires activation of the enone by elec-
involve the creation of two quaternary stereogenic tron-withdrawing groups, since it proceeds with enone
carbon centres in a rather hindered environment. The 8e only.
cyclization reaction between 8e and ethyl allenoate 5
Scheme 2. Synthesis of the dispiroACTHNUTRGNEUG[N 4.1.4.3]-7-thiotetradecanone 10 and the carbon analogue 12.
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Heterocyclic Spiranes and Dispiranes via Enantioselective Phosphine-Catalyzed [3+2]Annulations
Scheme 3. Diastereoselective oxidation of the spirocyclic
sulfides 8.
tive configurations of the sulfoxide group and the cy-
clopentene unit have been established by X-ray dif-
fraction studies on 9a (Figure 2).
X-ray data show that oxidation takes place exclu-
sively from the less hindered face of the dihydro-thio-
pyranone moiety, that is, from the face opposite to
Figure 1. ORTEP view of the bis-spiranic derivative 12
(CCDC 834027, these data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif).
Interestingly, the scope of the double [3+2]annula- the phenyl substituent of the spirocyclic substrate 8a.
tion process could be extended also to non-heterocy- Although diastereoselective oxidations of chiral sul-
clic substrates: an analogous bis-spiranic scaffold fides into the corresponding sulfoxides are largely
could be obtained from the cyclohexanone derivative documented,[17] the perfect diastereoselectivity ob-
11, where the double bonds are activated by the elec- served in the synthesis of 9 remains exceptional. It is
tron-withdrawing p-NO2C6H4 groups.
likely to be related to the well-defined, rigid and
An X-ray crystal structure of 12 (Figure 1) allowed highly disymmetric steric environment of the sulfur
the stereochemistry of the bis-spiranic moiety to be centre generated by the spirocyclic scaffold. Also,
established unambiguously.
In summary, the spiranic and bis-spiranic sulfides 8
and 10 are easily available in enantiomerically en-
riched form, via the [3+2]annulations as shown in
Table 2 and Scheme 2, respectively. The chiral catalyst
FerroPHANE proved to be able to induce effective
regio- and stereocontrol in both annulation steps lead-
ing to the stereocontrolled formation of sulfides with
unusual molecular scaffolds.
Overall, of the four types of cyclic enones that we
envisioned initially as potential substrates for phos-
phine promoted [3+2]cyclizations (Scheme 1), only
sulfoxide 4 failed to produce the corresponding [4,5]-
spirocycle in synthetically useful yields and selectivity.
A possible strategy to get round this limitation and
access spirocyclic sulfoxides, would be to carry out a
controlled oxidation of sulfides 8. We therefore inves-
tigated this alternative strategy also.
We were able to achieve the desired diastereoselec-
tive oxidations of sulfides 8 into the corresponding
sulfoxides 9, as shown in Scheme 3.
The experimental procedure which involves oxida-
tion of 8 with m-CPBA at 08C, affords sulfoxides 9 in
quantitative yields and total diastereoselectivity. By
this method, a whole range of enantiomerically en-
riched sulfoxides could be obtained easily, starting
Figure 2. ORTEP view of 9a (CCDC 834028, these data can
be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/
from the corresponding sulfides (Scheme 3). The rela- cif).
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Deepti Duvvuru et al.
FULL PAPERS
Flash column chromatography was performed using 40–63
mesh silica. The bis-arylidene ketones were prepared follow-
ing known procedures.[13,18,19] FerroPHANE was synthesized
according to our previous work.[4c]
Representative Procedure for the Catalytic
[3+2]Annulations of Ethyl Buta-2,3-dienoate 5 with
Enones 1–3 (Table 1 and Table 2)
Scheme 4. Sulfoxide 13 obtained by m-CPBA oxidation of
10.
Ethyl 2,3-butadienoate (0.20 mmol) was added to a mixture
of enone (0.20 mmol) and the phosphorus catalyst [PPh3,
(S)-t-Bu-Binepine or (S,S)-FerroPHANE, 0.020 mmol] in
degassed toluene (0.7 mL) under an argon atmosphere.
After 8 h stirring at the given temperature (see Scheme 2,
Table 1 and Table 2), an additional 0.20 mmol amount of
2,3-butadienoate was added and the solution was stirred
overnight at the same temperature. The crude mixture was
concentrated under vacuum and the final product was puri-
fied by flash chromatography on silica gel.
weak interactions between the functional groups of
the substrates and the oxidizing agent might contrib-
ute to the stereochemical control of these reactions.
This excellent steric discrimination shows promise for
future applications of the chiral sulfoxides 9, sulfides
8 and analogous spiranic heterocycles as chiral auxil-
iaries in enantioselective processes.
Finally, the same oxidation procedure has been ap-
plied to the synthesis of the dispiranic sulfoxide 13
shown in Scheme 4.
The highly hindered environment of the sulfur
centre in the bis-spiranic derivative 10, induces a
lower reaction rate with respect to the analogous oxi-
dations in Scheme 3. Nevertheless, the desired sulfox-
ide 13 could be obtained in acceptable yield and fully
characterized.
Ethyl 9-benzylidene-10-oxo-4-phenyl-7-thiaspiroACTHNUGRTNEUNG[4.5]dec-
1-ene-1-carboxylate (8a): Rf 0.3 (10% EtOAc/heptanes);
1H NMR (300 MHz, CDCl3): d=7.64 (bs, 1H), 7.40–7.20 (m,
10H), 7.09 (t, J=2.6 Hz, 1H), 4.25 (t, J=8.4 Hz, 1H), 4.18
(q, J=7.2 Hz, 2H), 3.75 (dd, J=14.7, 1.8 Hz, 1H), 3.67 (dd,
J=14.7, 2.7 Hz, 1H), 3.27 (d, J=14.3 Hz, 1H), 2.94 (dd, J=
8.5, 2.6 Hz, 2H), 2.74 (dd, J=14.3, 2.8 Hz, 1H), 1.28 (t, J=
7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=202.3 (C),
163.6 (C), 145.0 (CH), 141.7 (C), 138.4 (C), 135.5 (CH),
135.2 (C), 134.7 (C), 130.0 (CH), 128.9 (CH), 128.6 (CH),
128.4 (CH), 128.2 (CH), 127.3 (CH), 64.1 (C), 60.7 (CH2),
55.1 (CH), 36.2 (CH2), 32.2 (CH2), 30.1 (CH2), 14.1 (CH3);
IR: nmax =1706, 1593, 1492, 1454, 1371, 1329, 1262, 1246,
Conclusions
1109, 1028, 764, 751, 699 cmÀ1
; HR-MS (ESI): m/z=
In conclusion, we have demonstrated that phosphine-
promoted organocatalytic [3+2]annulations afford a
convenient access to chiral cyclic amines and sulfides
with unprecedented spiranic scaffolds. (S,S)-Ferro-
PHANE is a convenient chiral catalyst giving highly
enantioselective annulations of this compound class.
427.1342, calcd. for C25H24NaO3S [M+Na]+: 427.1344; [a]D22:
+353 (c 0.5, CHCl3); HPLC (Daicel CHIRACEL IA, 308C,
10% i-PrOH/n-heptane, 1 mLminÀ1, 295 nm) retention
times: 9.4 min (minor) and 13.0 min (major), 92% ee.
Ethyl 9-benzylidene-7-methyl-10-oxo-4-phenyl-7-azaspiro-
AHCTUNGTREG[NNUN 4.5]dec-1-ene-1-carboxylate (6): Rf 0.3 (15% EtOAc/hep-
1
Especially reactions on sulfides occur with very high tanes); H NMR (300 MHz, CDCl3): d=7.69 (bs, 1H), 7.45–
7.32 (m, 5H), 7.25–7.15 (m, 5H), 7.11 (t, J=2.6 Hz, 1H),
4.25–4.05 (m, 3H), 3.67 (d, J=14.4 Hz, 1H), 3.37 (dd, J=
14.4, 2.4 Hz, 1H), 2.92 (dt, J=8.1, 2.6 Hz, 2H), 2.64 (bs,
2H), 1.82 (s, 3H), 1.23 (t, J=7.2 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=201.7 (C), 164.0 (C), 146.0 (CH),
140.1 (C), 139.9 (C), 135.5 (CH), 133.3 (C), 130.7 (CH),
128.6 (CH), 128.5 (CH+C), 127.9 (CH), 126.8 (CH), 64.0
(C), 60.7 (CH2), 57.5 (CH2), 56.7 (CH2), 54.4 (CH), 45.5
(CH3), 36.7 (CH2), 14.2 (CH3); IR: nmax =1707, 1677, 1597,
diastereo- and enantioselectivity levels. Moreover,
spiranic chiral sulfoxides of the same series are easily
available from the corresponding sulfides via a quan-
titative and totally diastereoselective oxidation proce-
dure. A bis-spiranic C2-symmetrical sulfide and the
corresponding sulfoxide have also been prepared by
applying the same methods. Further studies will be
oriented towards the use of these new heterocyclic
derivatives as chiral auxiliaries in organic and organo-
metallic catalysis.
1492, 1446, 1369, 1328, 1264, 1172, 1107, 1050, 909, 728 cmÀ1
;
HR-MS (ESI): m/z=424.1908, calcd. for C26H27NNaO3 [M+
Na]+: 424.1889; [a]D22: +447 (c 0.9, CHCl3); HPLC (Daicel
CHIRACEL IA, 308C, 5% i-PrOH/n-heptane, 1 mLminÀ1,
295 nm): retention times: 12.5 (minor) and 14.2 min (major),
86% ee.
Experimental Section
Ethyl 9-benzylidene-10-oxo-4-phenyl-7-oxaspiroACTHNUGRTNEUNG[4.5]dec-
1-ene-1-carboxylate (7): Rf 0.35 (20% EtOAc/heptanes);
1H NMR (300 MHz, CDCl3): d=7.70 (bs, 1H), 7.35–7.27 (m,
3H), 7.25–7.10 (m, 7H), 7.05 (t, J=2.7 Hz, 1H), 4.65 (dd,
J=14.7, 1.5 Hz, 1H), 4.59 (dd, J=14.7, 2.1 Hz, 1H), 4.2–
General Remarks
All non-aqueous reactions were run under an argon atmos-
phere, by using standard techniques for manipulating air-
sensitive compounds. All reagents and solvents were of com-
mercial quality and were used without further purification.
4.05 (m, 3H), 3.89 (d, JAB =12.4 Hz, 1H), 3.84 (d, JAB
=
12.4 Hz, 1H), 2.91 (ddd, J=18.3, 9.3, 2.1 Hz, 1H), 2.80 (ddd,
412
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Heterocyclic Spiranes and Dispiranes via Enantioselective Phosphine-Catalyzed [3+2]Annulations
J=18.3, 10.2, 2.7 Hz, 1H), 1.17 (t, J=7.2 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=200.4 (C), 163.6 (C), 146.6 (CH),
138.7 (C), 138.6 (C), 136.1 (CH), 134.8 (C), 133.1 (C), 130.8
(CH), 129.4 (CH), 128.7 (CH), 128.5 (CH), 128.4 (CH),
127.3 (CH), 68.6 (CH2), 68.3 (CH2), 63.4 (C), 60.9 (CH2),
54.3 (CH), 35.8 (CH2), 14.2 (CH3); IR: nmax =2930, 1708,
1681, 1597, 1492, 1446, 1371, 1331, 1261, 1231, 1196, 1127,
1028, 751, 698 cmÀ1; HR-MS (ESI): m/z=411.1584, calcd.
for C25H24NaO4 [M+Na]+: 411.1572.
DCM (3 mL) at 08C under an argon atmosphere. The mix-
ture was stirred at 08C for 0.5 h. The reaction mixture was
diluted with CH2Cl2, then quenched with saturated NaHCO3
solution and washed with brine and water. The organic layer
was dried over MgSO4 and concentrated under vacuum to
afford the pure sulfoxides 9.
Ethyl 9-benzylidene-10-oxo-4-phenyl-7-thiaspiroACTHNUGRTNEUNG[4.5]dec-
1-ene-1-carboxylate 7-oxide (9a): Rf 0.3 (90% EtOAc/hep-
1
tanes); H NMR (300 MHz, CDCl3): d=7.80 (bs, 1H), 7.45–
7.35 (m, 3H), 7.32–7.25 (m, 5H), 7.20–7.10 (m, 2H), 7.06 (t,
J=2.6 Hz, 1H), 4.38 (dd, J=3.7, 2.6 Hz, 1H), 4.24–4.08 (m,
3H), 3.80 (dd, J=12.6, 2.1 Hz, 1H), 3.39 (dd, J=12.6,
3.7 Hz, 1H), 3.30 (d, J=12.7 Hz, 1H), 3.07 (ddd, J=18.6,
10.1, 2.1 Hz, 1H), 2.87 (ddd, J=18.6, 7.7, 3.1 Hz, 1H), 1.29
(t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=199.9
(C), 163.1 (C), 144.9 (CH), 143.5 (CH), 140.7 (C), 137.0 (C),
134.1 (C), 129.8 (CH), 129.6 (CH), 129.3 (CH), 129.0 (CH),
128.7 (CH), 128.5 (C), 64.6 (C), 61.3 (CH2), 55.8 (CH), 55.1
(CH2), 51.9 (CH2), 35.4 (CH2), 14.2 (CH3); IR: nmax =1700,
1591, 1446, 1371, 1329, 1243,1126,1105, 1040, 901, 733,
Synthesis of 10
Compound 10 was obtained by FerroPHANE-promoted
[3+2]cyclization of 8e with ethyl butadienoate 5, according
to the general procedure described above. Rf 0.3 (10%
1
EtOAc/heptanes); H NMR (300 MHz, CDCl3): d=8.08 (d,
J=8.9 Hz, 4H), 7.56 (d, J=8.9 Hz, 4H), 7.23 (t, J=2.6 Hz,
2H), 4.25 (q, J=6.9 Hz, 4H), 4.19 (dd, J=8.7, 2.4 Hz, 2H),
3.80 (d, J=13.7 Hz, 2H), 3.09 (ddd, J=19.2, 8.6, 2.5 Hz,
2H), 2.58 (dt, J=19.2, 2.7 Hz, 2H), 2.29 (d, J=13.7 Hz,
2H), 1.36 (t, J=7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3):
d=205.9 (C), 164.1 (C), 149.3 (C), 147.4 (CH+C), 137.9
(C), 129.9 (CH), 123.3 (CH), 65.8 (C), 61.1 (CH2), 50.5
(CH), 41.0 (CH2), 26.5 (CH2), 14.4 (CH3); IR: nmax =1706,
1597, 1518, 1346, 1278, 1109, 1070, 1018, 848, 747 cmÀ1; HR-
MS (ESI): m/z=629.1595, calcd. for C31H30N2NaO9S [M+
Na]+: 629.1570, found: ; [a]D22: +435 (c 0.7, CHCl3); HPLC
(Daicel CHIRACEL IA, 308C, 8% i-PrOH/n-heptane,
1 mLminÀ1, 295 nm): retention times: 26.4 (minor) and
29.2 min (major), >99% ee.
697 cmÀ1
;
HR-MS (ESI): m/z=421.1457, calcd. for
C25H25O4S [M+H]+ 421.1474; [a]22: +120 (c 0.3, CHCl3);
HPLC (Daicel CHIRACEL IA, 3D08C, 30% i-PrOH/n-hep-
tane, 1 mLminÀ1, 295 nm): retention times: 12.0 (minor) and
17.3 min (major), 90% ee. Compound 9a has been character-
ized by X-ray diffraction studies, registration number:
CCDC 834028. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Synthesis of the Bis-spiranic Cyclohexanone 12
References
Ethyl 2,3 butadienoate (0,45 mmol) was added to a mixture
of (2E,6E)-2,6-bis(p-nitrobenzylidene)-4-tert-butylcyclohexa-
none 11 (0.15 mmol) and FerroPHANE, II (10 mol%,
0.015 mmol) in degassed toluene (0.5 mL) under an argon
atmosphere. The solution was stirred at 808C for 60 h. The
crude mixture was concentrated under vacuum. The final
product was purified by flash chromatography on silica gel
[1] a) C. Zhang, X. Lu, J. Org. Chem. 1995, 60, 2906–2908;
b) X. Lu, C. Zhang, Z. Xu, Acc. Chem. Res. 2001, 34,
535–544; c) L.-W. Ye, J. Zhou, Y. Tang, Chem. Soc.
Rev. 2008, 37, 1140–1152.
[2] a) S. G. Pyne, K. Schafer, B. W. Skelton, A. H. White,
Chem. Commun. 1997, 2267–2268; b) L.-H. Shu, W.-Q.
Sun, D.-W. Zhang, S.-H. Wu, H.-M. Wu, J.-F. Xu, X.-F
Lao, Chem. Commun. 1997, 79–80; c) B. F. OꢁDonovan,
P. B. Hitchcock, M. F. Meidine, H. W. Kroto, R. Taylor,
D. R. M. Walton, Chem. Commun. 1997, 81–82;
d) A. T. Ung, K. Schafer, K. B. Lindsay, S. G. Pyne, K.
Amornraksa, R. Wouters, I. Van der Linden, I. Bies-
mans, A. S. J. Lesage, B. W. Skelton, A. H. White, J.
Org. Chem. 2002, 67, 227–233; e) T. Q. Pham, S. G.
Pyne, B. W. Skelton, A. H. White, J. Org. Chem. 2005,
70, 6369–6377; f) Y. Du, X. Lu, Y. Yu, J. Org. Chem.
2002, 67, 8901–8905; g) Y. Du, X. Lu, J. Org. Chem.
2003, 68, 6463–6465; h) X. Lu, Z. Lu, X. Zhang, Tetra-
hedron 2006, 62, 457–460; i) D. J. Wallace, R. L. Sidda,
R. A. Reamer, J. Org. Chem. 2007, 72, 1051–1054;
j) C. E. Henry, O. Kwon, Org. Lett. 2007, 9, 3069–3072;
k) J. L. Garcꢂa Ruano, A. Nunez, M. R. Martin, A.
Fraile, J. Org. Chem. 2008, 73, 9366–9371; l) X.-Y.
Guan, M. Shi, J. Org. Chem. 2009, 74, 1977–1981;
m) X.-C. Zhang, S.-H. Cao, Y. Wei, M. Shi, Chem.
Commun. 2011, 47, 1548–1550; n) Y.-Q. Zou, C. Li, J.
Rong, H. Yan, J.-R. Chen, W.-J. Xiao, Synlett 2011,
1000–1004.
1
with an EtOAc/heptane gradient (5:95 to 20:80). H NMR
(300 MHz, CDCl3): d=8.14 (d, J=8.4 Hz, 2H), 8.13 (d, J=
8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.4 Hz,
2H), 7.15 (dt, J=14.6, 2.3 Hz, 2H), 4.28 (q, J=7.1 Hz, 4H),
4.11 (d, J=8.7, 1H), 3.98 (d, J=8.7 Hz, 1H), 3.3–3.2 (m,
2H), 2.60 (d, J=19.3, 1H), 2.47 (d, J=19.3, 1H), 1.95 (t, J=
13.3 Hz, 1H), 1.64 (t, J=13.2 Hz, 1H), 1.55 (m, 1H), 1.38 (t,
J=7.1 Hz, 3H), 1.37 (t, J=7.1 Hz, 3H), 1.3 (m, 1H), 0.10 (s,
9H); 13C NMR (75 MHz, CDCl3): d=216.0 (C), 164.9 (C),
164.5 (C), 152.2 (C), 151.7 (C), 147.0 (C), 146.9 (C), 146.8
(CH), 145.7 (CH), 143.6 (C), 140.9 (C), 130.5 (CH), 130.2
(CH), 123.72 (CH), 64.9 (C), 62.8 (C), 60.9 (CH2), 60.8
(CH2), 54.8 (CH), 52.3 (CH), 42.5 (CH2), 41.2 (CH2), 38.0
(CH), 33.4 (CH2), 32.3 (C), 28.2 (CH2), 26.1 [CACHTNUGTRNEUNG(CH3)3], 14.4
(CH3); IR: nmax =2958, 1702, 1517, 1345, 1281, 1127, 1063,
850, 747 cmÀ1; HR-MS (ESI): m/z=667.2606, calcd. for
C36H40N2NaO9 [M+Na]+: 667.2632; [a]2D2: +68 (c 1.0,
CHCl3).
Synthesis of Sulfoxides 9
3-Chloroperoxybenzoic acid (0.12 mmol) in DCM (2 mL)
was added over 0.5 h to a solution of sulfide 8 (0.1 mmol) in
Adv. Synth. Catal. 2012, 354, 408 – 414
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413

Deepti Duvvuru et al.
FULL PAPERS
[3] For a review, see: A. Marinetti, A. Voituriez, Synlett
2010, 174–194.
Rev. 2007, 107, 5841–5883; e) M. C. CarreÇo, G.
Hernꢄndez-Torres, M. Ribagorda, A. Urbano, Chem.
Commun. 2009, 6129–6144.
[4] For selected examples, see: a) Z. Pakulski, O. M. Dem-
chuk, J. Frelek, R. Luboradzki, K. M. Pietrusiewicz,
Eur. J. Org. Chem. 2004, 3913–3918; b) J. E. Wilson,
G. C. Fu, Angew. Chem. 2006, 118, 1454–1457; Angew.
Chem. Int. Ed. 2006, 45, 1426–1429; c) A. Voituriez, A.
Panossian, N. Fleury-Brꢃgeot, P. Retailleau, A. Marine-
tti, J. Am. Chem. Soc. 2008, 130, 14030–14031; d) M.
Sampath, T.-P. Loh, Chem. Commun. 2009, 1568–1570;
e) M. Sampath, T.-P. Loh, Chem. Sci. 2010, 1, 739–742;
f) H. Xiao, Z. Chai, C.-W. Zheng, Y.-Q. Yang, W. Liu,
J.-K. Zhang, G. Zhao, Angew. Chem. 2010, 122, 4569–
4572; Angew. Chem. Int. Ed. 2010, 49, 4467–4470; g) X.
Han, S.-X. Wang, F. Zhong, Y. Lu, Synthesis 2011,
1859–1864; h) M. Neel, J. Gouin, A. Voituriez, A. Ma-
rinetti, Synthesis 2011, 2003–2009; i) Y. Fujiwara, G. C.
Fu, J. Am. Chem. Soc. 2011, 133, 12293–12297.
[13] a) M. S. Puar, G. C. Rovnyak, A. I. Cohen, B. Toeplitz,
J. Z. Gougoutas, J. Org. Chem. 1979, 44, 2513–2518;
b) R. Suresh Kumar, S. M. Rajesh, S. Perumal, P. Yo-
geeswari, D. Sriram, Tetrahedron: Asymmetry 2010, 21,
1315–1327; c) G. C. Rovnyak, R. C. Millonig, J.
Schwartz, V. Shu, J. Med. Chem. 1982, 25, 1482–1488.
[14] a-Regioisomers may be formed preferentially in analo-
gous annulations involving different substrate pairs: see
a) refs.[2g–i]; b) ref.[2m]; c) ref.[6a]; d) T. Q. Pham, S. G.
Pyne, B. W. Skelton, A. H. White, Tetrahedron Lett.
2002, 43, 5953–5956.
[15] The chiral phosphines shown hereafter afforded enan-
tiomeric excesses in the range 29–43%.
[5] G. Zhu, Z. Chen, Q. Jiang, D. Xiao, P. Cao, X. Zhang,
J. Am. Chem. Soc. 1997, 119, 3836–3837.
[6] a) B. J. Cowen, S. J. Miller, J. Am. Chem. Soc. 2007,
129, 10988–10989; b) A. Voituriez, A. Panossian, N.
Fleury-Brꢃgeot, P. Retailleau, A. Marinetti, Adv. Synth.
Catal. 2009, 351, 1968–1976.
[7] a) A. Voituriez, N. Pinto, M. Neel, P. Retailleau, A.
Marinetti, Chem. Eur. J. 2010, 16, 12541–12544; b) X.
Han, Y. Wang, F. Zhong, Y. Lu, J. Am. Chem. Soc.
2011, 133, 1726–1729; c) B. Tan, N. R. Candeias, C. F.
Barbas III, J. Am. Chem. Soc. 2011, 133, 4672–4675.
[8] a) N. Pinto, M. Neel, A. Panossian, P. Retailleau, G.
Frison, A. Voituriez, A. Marinetti, Chem. Eur. J. 2010,
16, 1033–1045; b) N. Pinto, P. Retailleau, A. Voituriez,
A. Marinetti, Chem. Commun. 2011, 47, 1015–1017.
[9] J. R. Dimmock, M. P. Padmanilayam, R. N. Puthucode,
A. J. Nazarali, N. L. Motaganahalli, G. A. Zello, J. W.
Quail, E. O. Oloo, H.-B. Kraatz, J. S. Prisciak, T. M.
Allen, C. L. Santos, J. Balzarini, E. De Clercq, E. K.
Manavathu, J. Med. Chem. 2001, 44, 586–593.
[16] For other synthetic approaches to polyspiranic scaf-
folds, see: a) ref.[13b]; b) J. Brugidou, H. Christol, Bull.
Soc. Chim. Fr. 1968, 1141–1144; c) B. M. Trost, Y. Shi,
J. Am. Chem. Soc. 1993, 115, 9421–9438; d) J. Leuger,
G. Blond, R. Frçhlich, T. Billard, G. Haufe, B. R. Lan-
glois, J. Org. Chem. 2006, 71, 2735–2739.
´
´
[17] E. Wojaczynska, J. Wojaczynski, Chem. Rev. 2010, 110,
4303–4356.
[18] a) M. S. Abaee, M. M. Mojtahedi, M. M. Zahedi, A. W.
Mesbah, N. M. Ghandchi, W. Massa Phosphorus Sulfur
Silicon Rel. El. 2007, 182, 2891–2895; b) M. S. Abaee,
M. M. Mojtahedi, M. M. Zahedi, R. Sharifi, Heteroat.
Chem. 2007, 18, 44–49; c) M. S. Abaee, M. M. Mojtahe-
di, M. M. Zahedi, Synlett 2005, 15, 2317–2320; d) G. C.
Rovnyak, V. Shu, J. Org. Chem. 1979, 44, 2518–2522;
e) N. J. Leonard, D. Choudhury, J. Am. Chem. Soc.
1957, 79, 156–160.
[19] a) Z.-G. Han, S.-J. Tu, B. Jiang, S. Yan, X.-H. Zhang,
S.-S. Wu, W.-J. Hao, X.-D. Cao, F. Shi, G. Zhang, N.
Ma, Synthesis 2009, 10, 1639–1646; b) H. N. Pati, U.
Das, S. Das, B. Bandy, E. De Clercq, J. Balzarini, M.
Kawase, H. Sakagami, J. W. Quail, J. P. Stables, J. R.
Dimmock, Eur. J. Med. Chem. 2009, 44, 54–62; c) L.
Yuan, B. G. Sumpter, K. A. Abboud, R. K. Castellano,
New. J. Chem. 2008, 32, 1924–1934; d) J. Krapcho, C. F.
Turk, J. Med. Chem. 1979, 22, 207–210.
[10] R. Suresh Kumar, S. Perumal, K. Arun Shetty, P. Yo-
geeswari, D. Sriram, Eur. J. Med. Chem. 2010, 45, 124–
133.
[11] a) P. Melchiorre, M. Marigo, A. Carlone, G. Bartoli,
Angew. Chem. 2008, 120, 6232–6265; Angew. Chem.
Int. Ed. 2008, 47, 6138–6171; b) S. Bertelsen, K. A Jør-
gensen, Chem. Soc. Rev. 2009, 38, 2178–2189; c) F.
Fache, E. Schulz, M. L. Tommasino, M. Lemaire,
Chem. Rev. 2000, 100, 2159–2231; d) S. E. Denmark,
N. D. Gould, L. M. Wolf, J. Org. Chem. 2011, 76, 4260–
4336.
[12] a) I. Fernꢄndez, N. Khiar, Chem. Rev. 2003, 103, 3651–
3705; b) H. Pellissier, Tetrahedron 2007, 63, 1297–1330;
c) M. Mellah, A. Voituriez, E. Schulz, Chem. Rev. 2007,
107, 5133–5209; d) E. M. McGarrigle, E. L. Myers, O.
Illa, M. A. Shaw, S. L. Riches, V. K. Aggarwal, Chem.
414
asc.wiley-vch.de
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 408 – 414