Modular pyridine-type P,N-ligands derived from monoterpenes: Application in asymmetric Heck addition

Article abstract of DOI:10.1016/S0040-4039(01)00369-0

Novel (diphenylphosphinophenyl)pyridine ligands (+)-8, (+)-15, (-)-21, and (-)-26 were synthesized from (-)-β-pinene, (+)-3-carene, (+)-2-carene, and (-)-α-pinene, respectively, via Kro?hnke annulation as the key step, and shown to effect ≤88% ee in Heck addition (27→28). Ligands (+)-15 and (-)-21 are quasi-enantiomeric; ligands 8 and 26 can be prepared in both enantiomeric forms from (+)- and (-)-enantiomers of α- and β-pinene, respectively.

Full text of DOI:10.1016/S0040-4039(01)00369-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3045–3048
Modular pyridine-type P,N-ligands derived from monoterpenes:
application in asymmetric Heck addition
Andrei V. Malkov,* Marco Bella,† Irena G. Stara´‡ and Pavel Kocˇovsky´*
Department of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK
Received 26 January 2001; accepted 28 February 2001
Abstract—Novel (diphenylphosphinophenyl)pyridine ligands (+)-8, (+)-15, (−)-21, and (−)-26 were synthesized from (−)-b-pinene,
(+)-3-carene, (+)-2-carene, and (−)-a-pinene, respectively, via Kro¨hnke annulation as the key step, and shown to effect 588% ee
in Heck addition (27“28). Ligands (+)-15 and (−)-21 are quasi-enantiomeric; ligands 8 and 26 can be prepared in both
enantiomeric forms from (+)- and (−)-enantiomers of a- and b-pinene, respectively. © 2001 Elsevier Science Ltd. All rights
reserved.
Transition metal complexes with heterobidentate lig-
ands, such as (phosphinoaryl)oxazolines,1 MOP,2
QINAP,3 and MAP,4 are valuable catalysts for a num-
ber of asymmetric reactions, particularly in those areas
where the traditional C2-symmetrical ligands fail.1–5
Herein, we report on the synthesis of novel (phosphi-
noaryl)pyridine P,N-ligands, where the chirality is
introduced by annulation to a monoterpene segment.6
This approach is based on our experience in the synthe-
sis of the C2-symmetrical bipyridine ligand PINDY, in
which the pyridine units were annulated to the chiral
blocks originating from (−)-b-pinene.7,8
In the synthesis of the first (phosphinoaryl)pyridine
(+)-8 (Scheme 1), (+)-nopinone (+)-2, obtained from
(−)-b-pinene (−)-19a by oxidative cleavage (cat. OsO4,
Me3NO, Py, NaIO4, t-BuOH–H2O, rt, 30 min, then
reflux for 2 h; 66%),7,10 was condensed with ethyl
formate (HCO2Et, MeONa, toluene, rt, 10 h) to gener-
ate 3 (75%). Subsequent transaldolization (37% CH2O
I2
1. HCO2Et
MeONa
N+
C5H5N
X
I−
+
2. CH2O,
O
O
X
O
Na2CO3
F
(−)-1, X = CH2
(+)-2, X = O
3, X = OH
4, X = H
F
6
5
AcONH4, 90 oC
Ph2PH
t-BuOK
N
N
Ph2P
F
(+)-8
7
Scheme 1.
* Corresponding authors. E-mail: amalkov@chem.gla.ac.uk; p.kocovsky@chem.gla.ac.uk
†
Exchange student from the Dipartimento di Chimica and Centro CNR di Studio per la Chimica delle Sostanze Organiche Naturali, Piazzale
Aldo Moro, 5, Box No. 34, Roma 62, 00185 Rome, Italy.
On leave from the Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo n. 2, 166 10
Prague 6, Czech Republic.
‡
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00369-0

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A. V. Malko6 et al. / Tetrahedron Letters 42 (2001) 3045–3048
ether) produced the cis-derivative (+)-11 (98%).16
Claisen condensation of (+)-11 (HCO2Et, MeONa,
toluene, rt, 10 h; 76%), followed by transaldolization
(37% CH2O in H2O, Na2CO3, ether, rt, 2 h; 90%) gave
(+)-13, whose treatment with Kro¨hnke salt (5,
AcONH4, AcOH, 90°C, 3 h) furnished (+)-14 (60%), in
which the fluorine was replaced by phosphorus (Ph2PH,
t-BuOK, 18-crown-6, THF, rt, 48 h) to afford ligand
(+)-15 (83%).
P
P
N
N
A
B
Figure 1.
in H2O, Na2CO3, ether, rt, 2 h) afforded 4 (90%),11
whose condensation with Kro¨hnke reagent (5,
AcONH4, AcOH, 90°C, 3 h), obtained from 6 on
iodination in pyridine (I2, pyridine, 100°C, 2 h; 47%),12
produced (+)-7 (47%).12 Treatment of (+)-7 with Ph2PK
(Ph2PH, t-BuOK, 18-crown-6, THF, rt, 48 h)13
afforded the desired phosphine (+)-8 (49%).
In a related procedure (Scheme 3), (+)-2-carene (+)-169c
was epoxidized (MCPBA, ether, rt, 12 h; 85%), and the
resulting 1717 was isomerized (LDA, 3 equiv, THF, 0°C
to rt, 6 h) to give 18 (53%),18,19 whose oxidation
[PhI(OAc)2, TEMPO, CH2Cl2, rt, 5 h]20 afforded 19
(83%). Kro¨hnke annulation (5, AcONH4, AcOH, 90°C,
3 h) produced (−)-20 (60%), which was then converted
into (−)-21 (Ph2PH, t-BuOK, 18-crown-6, THF, rt, 48
h; 74%).
In a metal complex of (+)-8, the upper-left front octant
will be severely hindered by the CMe2 group (A in Fig.
1) but the lower-left octant will also be partly shielded
by the CH2 group of the cyclobutane ring. The latter
drawback would be eliminated in the cyclopropane
ligand B, where the CH2 group is absent, leaving the
lower-left octant free.14
Finally, yet another ligand architecture can be envis-
aged for an analogue where the terpene bridge is shifted
by one carbon, leaving the ‘benzylic’ position amenable
to alkylation.8 This ligand type, namely (−)-26 (Scheme
4), was synthesized from (+)-pinocarvone (+)-22,21
obtained either by allylic oxidation of (−)-b-pinene
(−)-1 (SeO2, CCl4, reflux, 24 h, 27%),22 or via the
ene-reaction of (−)-a-pinene (−)-23 with singlet oxygen
(hw, O2, TPP, pyridine, DMAP, Ac2O, CH2Cl2, rt, 2
As a building block for the cyclopropane moiety, we
chose (+)-3-carene (+)-99b (Scheme 2). Allylic oxidation
[O2, CrO3 (1 mol%), pyridine (5 mol%), rt, 24 h]15 gave
(−)-10 (20%), whose hydrogenation (H2, 5% Pd/C,
1. HCO2Et
O2
H2, Pd/C
X
MeONa
CrO3
2. CH2O,
Na2CO3
O
O
O
(−)-10
(+)-11
(+)-9
12, X = OH
13, X = H
5, AcONH4
90 oC
Ph2PH
t-BuOK
N
N
Ph2P
(+)-15
F
14
Scheme 2.
PhI(OAc)2
TEMPO
O
HO
O
MCPBA
LDA
17
18
(+)-16
19
5, AcONH4
90 oC
Ph2PH
t-BuOK
N
N
F
Ph2P
(−)-21
20
Scheme 3.

A. V. Malko6 et al. / Tetrahedron Letters 42 (2001) 3045–3048
3047
following acronyms: PINPHOS for (+)-8, (+)- and (−)-
CANPHOS for (+)-15 and (−)-21, respectively, and
iso-PINPHOS for (−)-26.
1O2, hν
SeO2
TPP
(cat.)
O
(−)-1
(+)-22
(−)-23
1. 5, AcONH4
Acknowledgements
2. BuLi, then MeI
The authors would like to thank the University of
Glasgow for generous financial support and the Con-
siglio Nazionale delle Ricerche, Rome, Italy, for sup-
port to M.B. (Short Term Mobility Program).
Ph2PK
N
N
R
F
Ph2P
(−)-24, R = H
(−)-26
(−)-25, R = Me
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3048
A. V. Malko6 et al. / Tetrahedron Letters 42 (2001) 3045–3048
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