Carbenoid addition to phenols to give cycloheptatrienols. Stereochemical regulation and ligand-dependent switching of chemoselectivity

Article abstract of DOI:10.1246/cl.2007.314

Cycloheptatrienols were prepared stereoselectively by the intramolecular Buechner reaction of phenols using a 2,4-pentane-diol tether of suitable stereochemistry, where the intrinsically favorable O-H insertion is effectively suppressed. Copyright

Full text of DOI:10.1246/cl.2007.314

314
Chemistry Letters Vol.36, No.2 (2007)
Carbenoid Addition to Phenols to Give Cycloheptatrienols.
Stereochemical Regulation and Ligand-dependent Switching of Chemoselectivity
Chun Young Im, Tadashi Okuyama, and Takashi Sugimuraꢀ
Graduate School of Material Science, Himeji Institute of Technology, University of Hyogo,
Kohto, Kamigori, Ako-gun, Hyogo 678-1297
(Received December 1, 2006; CL-061419; E-mail: sugimura@sci.u-hyogo.ac.jp)
2
4
7
5
Cycloheptatrienols were prepared stereoselectively by the
intramolecular Buchner reaction of phenols using a 2,4-pentane-
¨
diol tether of suitable stereochemistry, where the intrinsically
favorable O–H insertion is effectively suppressed.
N2
Rh2L4
100%
O
O
O
O
O
(2)
O
OH
O
(2R,4S)-1 (1a)
(5R,7S)-2 (2a)
(5S,7S)-2 (2b)
2
4
Metal carbenoid generated from a diazo compound is a
useful species having both sufficient reactivity and reasonable
selectivity with various functional groups.1 Selectivity in the
reaction with a multi-functionalized substrate depends on the
structure of the diazo compound and the catalyst employed,
but the reactivity of the functional group is more influential than
the nature of the carbenoid.2 The O–H insertion reaction is very
fast, and usually preferred to other carbenoid reactions.3 Phenol
offers a typical example; only the O–H insertion proceeds,
N2
Rh2L4
O
6'
3'
O
O
9
6
O
O
O
OH
O
13
HO
HO
(2S,4S)-1 (1b)
O
+
(3)
11aR
O
1R
3
4
F–
TBS-imidazol/
DMAP
but the addition to the aromatic ꢀ-bond (Buchner reaction)
¨
Rh2(OCOCF3)4
(quant.)
or C–H insertion does not occur irrespective of the carbenoid
structure, reaction conditions, or substituent on the phenyl ring
(eq 1).4–7
TBS analogue of 1b
3'
+
4'
6 : 4
Structures of 3 and 4 were confirmed by using their TBS an-
alogues. When the hydroxy group in 1b was protected with TBS
prior to the reaction, a mixture of two products, 30 and 40, the
TBS analogues of 3 and 4, was obtained quantitatively in a ratio
of 61:39. Although deprotection of 30 and 40 with TBAF did not
give 3 or 4 leading solely to the decomposed products, the TBS
protection of a mixture of 3 and 4 could lead to these TBS ana-
logues that were identical to 30 and 40.
Several other catalysts were employed for the reaction. The
total yields and compositions of the intramolecular adducts 2–4
are summarized in Table 1. Rh2(OCOC3F7)4 generates a very re-
active carbenoid due to the strongly electron-accepting ligands,
and in fact, the reaction completed in a short time to give the
internal adducts in good yields as was with Rh2(OCOCF3)4.
The O–H insertion product 2b was obtained only in 6%, but
H
OR
OH
OH
O
O
O
ROCOCHN2
cat.
(1)
COOR
COOR
Bu¨chner reactions
O−H insertion
During our study of asymmetric syntheses using 2,4-pen-
tanediol as a chiral tether,8 Rh2(OCOCF3)4-catalyzed reaction
of diazo compound (2R,4S)-1 (1a) was found to give 2a in
a quantitative yield via the intramolecular O–H insertion,
though this reaction does not generate any new chiral center
(eq 2).9 In contrast, the reaction of a diastereomeric substrate,
(2S,4S)-1 (1b) led to the novel Buchner reaction, overcoming
¨
the O–H insertion, to yield chiral cycloheptatrienols 3 and
4 stereoselectively (eq 3), which is detailed in this communica-
tion.
Stereochemically pure diazo compound 1b was subjected
to the Rh2(OCOCF3)4-catalyzed reaction in chloroform-d at
room temperature. The reaction mixture mostly consisted of
three intramolecular products, as analyzed by 1H NMR at
the remaining major part was a mixture of the two Buchner prod-
¨
ucts 3 and 4. In contrast, the intramolecular reactions with less
electrophilic catalysts were slow and intermolecular reaction
Table 1. Total yields of the internal adducts and their composi-
tions in the reaction of 1ba
600 MHz. The two major products were those of the Buchner
¨
reaction 3 and 4, while the O–H insertion product 2b was minor.
The mixture was unchanged at least for 1 h at room temperature,
but 2b was the only isolable compound by a silica gel column.
Stereochemistries of 3 and 4 were assigned to 11aR and 1R,
respectively, by the NOE experiments (H-9 to H-11a, and H-6
to H-13). Throughout the study, no diastereomers of 3 or 4 were
Composition/%
Yield
/%
Catalyst
2b
3
4
Rh2(OCOC3F7)4
Rh2(OCOCF3)4
Rh2(OAc)4
Rh2(OCOC7H15)4
Rh2[(5S)-MEPY]4
97
92
21
14
50
6
10
77
42
44
0
52
46
23
37
0
63
100
0
0
detected in any reactions (<2% of 3 or 4). Thus, the Buchner
¨
b
reaction of 1b is stereoselective to proceed at the 10,60- and
40,50-positions.
aDetermined by 1H NMR. bMEPY = methyl 2-oxopyrroli-
dine-5-carboxylate.
Copyright Ó 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.2 (2007)
315
the keto isomer of the Buchner product produced by the
¨
(a)
HO
(b)
OH
(c)
(d)
regio- and stereoselective addition at 30,40-position as shown in
Figure 1c. Once again, the reaction with Rh2(MEPY)4 resulted
only in the O–H insertion to give 7a in 55% yield with some
accompanying intermolecular side products. In the case of 5b
carrying (2S,4S)-tether, the carbenoid part placed closer position
to the hydroxy group (Figure 1d). The reaction with Rh2-
Rh2L4
Rh2L4
6'
2'
O
O
O
O
O
O
4'
4'
OH
OH
O
O
O
O
O
O
Rh2L4
Rh2L4
A
B
C
D
(OCOCF ) gave a mixture of 7b and the Buchner products12
¨
Figure 1. The most probable conformations of the carbenoids
A, B, C, and D generated from 1a, 1b, 5a, and 5b, respectively.
3 4
in a ratio of 50:50 (61%). Use of Rh2(MEPY)4 catalyst changed
the ratio to 97:3 (80%).
with contaminated water became dominant. Among the intramo-
lecular reactions, the O–H insertion to give 2b was the major
process and formation of 3 was not observed. A catalyst having
carboxamidate ligands, Rh2(MEPY)4, resulted exclusively in
the O–H insertion.10 The reaction of 1a was reinvestigated with
varied catalysts, but the O–H insertion product 2a was the only
intramolecular adduct in any cases.
The present study disclosed that the chiral tether consisting
of 2,4-pentanediol controls the reaction region to realize switch-
ing of the functional-group selectivity by the carbenoid ligand
when the stereochemistry of the tether is proper. Stereoselective
formation of cycloheptatrienols, 3 and 4, is remarkable because
it is difficult to achieve by other conventional methods due to
the unstable enol structure.13 The reaction control by the
prearranged conformation of the reactant is one of characteristic
features of the chiral tethered intramolecular reaction and may
be governed by the principle of least motion.14
Formation of the Buchner products with 1b is outstanding
¨
because the carbenoid part is accessible to the internal hydroxy
group as demonstrated with the carboxamidate catalyst. The
formation of 3 and 4 and their stereochemistries are explainable
by the conformation of the carbenoids. The most probable con-
formers generated from 1a and 1b are illustrated in Figures 1a
and 1b.11 The geometries are flexible, but sufficiently regulated
by chiralities on the tether. The face of the aromatic group to be
added is determined by the orientation of the hydroxy group that
sticks out to the less hindered space. The carbenoid part in A is
close and easily accessible to the hydroxy group, while that in B
is distant from it. When the carbenoid part in B is very reactive
with perfluorocarboxylate ligands, it is intercepted by the
aromatic ꢀ-electrons at closer 10,60- or 40,50-positions in place
of the O–H insertion, while the interception becomes inefficient
with the less reactive carbenoid carrying the carboxamidate.
This work was supported by a Grant-in-Aid for Scientific
Research (B) 16350026 by JSPS.
References and Notes
1
G. Maas, in Topics in Current Chemistry, Springer-Verlag, Berlin,
1987, Vol. 137, pp. 75–253; M. P. Doyle, M. A. McKervey, T. Ye,
Modern Catalytic Methods for Organic Synthesis with Diazo
Compounds, Wiley, New York, 1998; See also, Modern Rhodium-
Catalyzed Organic Reactions, ed. by P. A. Evans, Wiley-VHC,
Weinheim, 2005.
2
For examples, see: A. Padwa, D. J. Austin, A. T. Price, M. A.
Semones, M, P. Doyle, M. N. Protopopova, W. R. Winchester, A.
Tran, J. Am. Chem. Soc. 1993, 115, 8669; G. G. Cox, C. J. Moody,
D. J. Austin, A. Padwa, Tetrahedron 1993, 49, 5109; A. Padwa,
D. J. Austin, Angew. Chem., Int. Ed. Engl. 1994, 33, 1797; J. S. Clark,
A. G. Dossetter, Y.-S. Wong, R. J. Twonsend, W. G. Whittingham,
C. A. Russell, J. Org. Chem. 2004, 69, 3886.
The switching mechanism between the OH and the Buchner
¨
reactions by the prearranged conformation of the carbenoids is
confirmed by the reaction with 60-methyl analogues 5a and 5b,
where 60-methyl group is bulkier than 20-hydroxy group, and
thus the methyl is placed at the outer position to bring the
hydroxy inner as illustrated in Figures 1c and 1d.
6
3
4
D. J. Miller, C. J. Moody, Tetrahedron 1995, 51, 10811.
D. Haigh, Tetrahedron 1994, 50, 3177; G. G. Cox, D. J. Miller,
C. J. Moody, E.-R. H. B. Sie, J. J. Kulagowski, Tetrahedron 1994,
50, 3195.
2
Rh2(OCOCF3)4
or
4
5
6
Z. Qu, W. Shi, J. Wang, J. Org. Chem. 2004, 69, 217.
N2
Some exceptions are known in the intramolecular reaction where the
carbenoid is not accessible to the OH. C. Iwata, M. Yamada, Y.
Shiono, K. Kobayashi, H. Okada, Chem. Pharm. Bull. 1980, 28,
1932; C. Iwata, K. Miyashita, T. Imao, K. Masuda, N. Kondo, S.
Uchida, Chem. Pharm. Bull. 1985, 33, 853.
6'
O
Rh2(OAc)4
O
O
O
O
9
O
4'
2' OH
O
Rh2(MEPY)4
1R
(2R,4S)-5 (5a)
7
For example, 2-methoxyphenol and 3-methoxyphenol have electron-
rich aromatic ring, but resulted only in the O–H insertion with ethyl
diazoacetate irrespective of the rhodium catalyst.
6a
(4)
2
4
N2
8
9
T. Sugimura, Eur. J. Org. Chem. 2004, 1185.
C. Y. Im, T. Okuyama, T. Sugimura, Chem. Lett. 2005, 34, 1328.
Rh2L4
O
O
O
O
O
O
3 Bu¨chner
adducts
+
10 Due to the availability, this chiral catalyst was employed. Achiral
Rh2(cap)4 also gave only 2b, but in a low 35% yield.
O
OH
11 The structures were drawn based on the conformations of the
corresponding diazo esters calculated at the PM5 level using a confor-
mational analyzer, Fujitsu, CONFLEX V5.
(2S,4S)-5 (5b)
7a or 7b
As expected from the distant position of the hydroxy group
in C, the reaction of 5a carrying (2R,4S)-tether with Rh2-
(OCOCF3)4 did not give any O–H insertion product 7a, but
afforded 6a as a sole intramolecular product (eq 4). The yield
of 6a was only 14% owing to its instability under the reaction
conditions. The yield became better 47%, without formation of
7a, wen the catalyst was Rh2(OAc)4. The structural assignment
of 6a was based on the COSY spectra and the NOE between
6-Me and 9-Me. The structure determined is agreeable with
12 The Buchner products include one keto-type isomer and two
¨
cycloheptatrienols in a ratio of 12:24:64. The structures were not
determined yet.
13 Cycloheptatrienols are enols, and can be generated by the kinetic
protonation of the corresponding enolate, but such
a method
could not be applied to the stereoselective synthesis because of the
instability and quick epimerization. T. Sugimura, W. H. Kim, M.
Kagawa, T. Okuyama, Org. Lett. 2002, 4, 2059.
14 F. O. Rice, E. Teller, J. Chem. Phys. 1938, 489.
Published on the web (Advance View) January 27, 2007; doi:10.1246/cl.2007.314