Enantioselective β-lactone formation from phenyldiazoacetates via catalytic intramolecular carbon-hydrogen insertion

Article abstract of DOI:10.1055/s-2001-14635

Dirhodium(II) catalysts with chiral carboxylate or carboxamidate effectively promote β-lactone formation from phenyldiazoacetates in high yield and with up to 63% ee.

Full text of DOI:10.1055/s-2001-14635

LETTER
967
Enantioselective -Lactone Formation from Phenyldiazoacetates via Catalytic
Intramolecular Carbon-Hydrogen Insertion
Michael P. Doyle,* Eric J. May
Department of Chemistry, University of Arizona, Tucson, Arizona 85723, USA
Fax +1 520 6264815; E-mail: mdoyle@u.arizona.edu
Received 26 January 2001
compounds 4 and 5 (Table 1). Here, insertion into the
Abstract: Dirhodium(II) catalysts with chiral carboxylate or car-
3
1
°C H bond was favored over insertion into one of six
°C H bonds despite the additional strain introduced by
boxamidate effectively promote -lactone formation from phenyl-
diazoacetates in high yield and with up to 63% ee.
formation of a four- rather than a five-membered ring.
Traces of 3, mainly the trans-disubstituted lactone, were
observed, but the overall difference in reactivity could be
estimated to be greater than 50:1. Products were identified
by spectroscopic analysis with reference to literature re-
Key words: enantioselective carbon-hydrogen insertion, chiral
dirhodium(II) catalysts, phenyldiazoacetates, -lactones
Dirhodium(II) catalyzed intramolecular carbon-hydrogen
insertion reactions originating with diazocarbonyl com-
pounds have enjoyed wide popularity for the synthesis of
12
ports of the same compounds.
1
-4
cycloalkanones, lactones, and lactams. They exhibit a Table 1 Enantioselectivity in Carbon-Hydrogen Insertion Reac-
a
tions of Isopropyl Phenyldiazoacetate
high preference for the formation of five-membered rings
5
and, in the absence of conformational restrictions, reac-
tivity follows the order tertiary> secondary>> primary.6
There are few examples of insertion reactions favoring
1
,7-9
ring sizes other than five in these reactions,
even when
1
0
electronic influences would justify them. Recently,
Davies and coworkers have demonstrated that aryldiaz-
oacetates exhibit much higher levels of selectivity in C H
insertion reactions. Based on this report and other indi-
cators of reactivity/selectivity, we have searched for car-
1
1
1
bon-hydrogen insertion reactions that could provide the
formation of four-membered ring -lactones in reasonable
yields and with catalyst-directed enantiocontrol.
a
Reactions were performed in refluxing CH Cl , unless specified
2
2
The first substrate tested was isopropyl phenyldiazoace-
tate, and we were surprised to find that the corresponding
b
otherwise, using 1.0 mol% of catalyst. Yield of product after separa-
tion of catalyst (up to 70% yield after chromatographic purification).
-
lactone was virtually the sole product in reactions that
c
Enantiomer separation and analyses were performed on a 25-cm,
were catalyzed by rhodium acetate and by dirhodium(II) 4.6-mm (R,R)-WHELK-O column using 5% EtOAc in hexanes (8.2
d
and 9.0 min for the individual enantiomers). Reaction performed in
refluxing pentane.
Ph
Me
Ar
COOCHMe
2
Reactions catalyzed by chiral dirhodium(II) compounds,
2 4
Rh L
Me
O
O
4
either the Rh (S-DOSP) catalyst of Davies or our own
Me
Ar
2
4
N
2
O
O
13,14
chiral azetidinone-ligated catalysts,
generally resulted
1
2
3
in -lactone product in high yield but with only modest
enantioselectivities. The use of Rh (S-DOSP) produced
2
4
product with the highest% ee value, especially when the
reaction was performed in pentane. Reactions with azeti-
dinone-ligated catalysts in pentane provided no obvious
COOR
O
O
N
O
4Rh2
Rh
4 2
N
advantages over reactions performed in CH Cl .
SO
2
Ar
2
2
An attempt was made to determine the electronic influ-
ence of aryl substituents from aryldiazoacetates on enan-
tiocontrol. However, significantly lower product yields
4
4
4
4
4
a: R = Me, Rh
2
(4S-MEAZ)
(4S-IBAZ)
(4S-BNAZ)
11, Rh (4S-CHAZ)
CMe , Rh (4S-NEPAZ)
4
4
25
Rh (S-DOSP)4
6 4
5: Ar = p-C12H C H ,
i
b: R = Bu, Rh
2
4
2
c: R = Bn, Rh
d: R = cC
e: R = CH
2
4
were obtained with Ar = p-MeOC H – a substituent that,
6
H
2
4
6
4
11,15,16
based on published reports by Davies,
we thought
2
3
2
would lead to modest changes in enantioselectivity,% ee
Scheme 1
Synlett 2001 SI, 967–969 ISSN 0936-5214 © Thieme Stuttgart · New York

9
68
M. P. Doyle, E. J. May
LETTER
values were considerably lower than those reported in Ta-
O
O
ble 1 (33% ee with 5). However, with Ar = p-MeC H ,
Rh
6
4
Ph
R'
Rh (S-DOSP) gave the corresponding -lactone in 77%
2
4
R
yield with 48% ee, but Rh (S-MEAZ) gave product in
H
2
4
lower yield (34%) and with lower enantioselectivity (27%
ee). The reason for this apparent discrepancy is as yet un-
resolved.
9
the configuration of the -lactone product would be R.
When R and R’are not identical, one can expect a diaste-
reomeric product distribution that reflects the relative sta-
bilities of attached carbene/catalyst config-uration. This is
effectually represented in results from diazo decomposi-
tion of (S)-(+)-2-octyl phenyldiazo-acetate (10) from
which two diastereomeric -lactone products (11 and
Diazo decomposition of cyclohexyl diazoacetate produc-
es the -lactone products virtually exclusively. The cor-
7
responding -lactone, if formed at all, is a very minor
product. In contrast, diazo decomposition of cyclohexyl
phenyldiazoacetate 6 gives the corresponding -lactone
1
7
product 7 with near exclusivity (Table 2), and the cata-
lyst had virtually no influence on regioselectivity. Here,
enantioselectivities were higher than those obtained with
isopropyl phenyldiazoacetate. Comparable results were
obtained with cis-4-methylcyclohexyl phenyl-diazoace-
tate [with Rh (4S-MEAZ) in CH Cl : 74% yield, 44% ee;
19
1
2) are formed in good yields (Table 3). -Lactone prod-
ucts were, at best, trace constituents of the reaction mix-
ture. As expected, changing catalyst configurations,
Rh (4S-MEAZ) and Rh (4R-MEAZ) , resulted in mod-
2
4
2
4
2
4
2
2
est, but measurable, differences in diastereoselection in-
dicative of match/mismatch in catalyst-substrate
with Rh (S-DOSP) in pentane: 56% yield, 44% ee].
2
4
interactions. Surprisingly, the 11:12 ratio with Rh (S-
2
DOSP) was opposite to that with the 4S- azetidinone-li-
gated dirhodium(II) catalysts, and the reason for this is un-
known.
4
Rh2L4
Ph
COO
N2
6
O
O
Table 3 Diastereoselectivity in Carbon-Hydrogen Insertion Reac-
tions of (S)-(+)-2-Octyl Phenyldiazoacetate
O
+
O
a
Ph
Ph
7
8
Scheme 2
Table 2 Enantioselectivity and Regioselectivity in Carbon-Hydro-
a
gen Insertion Reactions of Cyclohexyl Phenyldiazo-acetate
a
b
Reactions were performed as described in Table 1. Yield after of re-
c
1
moval of catalyst. Determined by H NMR analysis and confirmed
by GC on a SPB-5 column operated at 100 °C. Column chromato-
d
graphy on silica (2.5-10% EtOAc in hexanes) allowed isolation of 11
e
(
28% yield) and 12 (57% yield) as separate products. Reaction per-
formed in refluxing pentane.
Overall, dirhodium(II) catalysts are surprisingly selective
O
a
Reactions were performed as described in Table 1. b Product yield
Ph
O
after separation of catalyst (up to 53% yield of 7 after chromatogra-
phic purification). Enantiomer separation and analyses were perfor-
Rh2L4
N2
c
med on a 25-cm, 4.6-mm (R,R)-WHELK-O column using 5% EtOAc
10
d
in hexanes (8.2 and 9.1 min for the individual enantiomers). Deter-
1
O
O
mined by H NMR of unique spectral regions for 7 (ref. 17) and 8 (ref.
e
Ph
1
8). Reaction performed in refluxing pentane.
H
O
O
H
+
Ph
1
1
12
In each C H insertion reaction presented thus far the
chiral center that is generated is the original diazo-carbon
atom with a probable transition state orientation that is de-
picted in 9. When reactions of 1, 6, and their analogs R
and R’are identical and, if insertion occurs as shown in 9,
Scheme 3
for -lactone formation, affording these products in high
Synlett 2001, SI, 967–969 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Enantioselective -Lactone Formation from Phenyldiazoacetates
969
yield, although with modest enantiocontrol. However, acknowledged. We are grateful to Professor Huw M. L. Davies for
providing us with a generous sample of Rh (S-DOSP) . This letter
when a tertiary C H bond is available that could result in
a -lactone product, as is the case with isobutyl phenyldia-
zoacetate (13), only the -lactone product is observed (Ta-
ble 4). Here use of the chiral azetidinone- ligated catalysts
gave comparable% ee values for the insertion product (14)
to results from Rh (S-DOSP) in pentane. Clearly, the
2
4
is dedicated to Professor Ryogi Noyori, whose insightful contribu-
tions to the development of asymmetric catalysis for metal carbene
transformations has led us to fruitful discoveries.
References and Notes
2
4
presence of a tertiary C H bond directs C H insertion
with phenyldiazoacetates to a far greater extent than that
found with diazoacetates alone.
(
1) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds: From
Cyclopropanes to Ylides; Wiley, New York, 1998.
(
2) Doyle, M. P.; McKervey, M. A. J. C. S. Chem. Commun.
1
997, 983. Doyle, M. P.; Forbes, D. C. Chem. Rev. 1998, 98,
911.
(3) Padwa, A.; Austin, D. J. Angew. Chem. Int. Ed. Engl. 1994,
Table 4 Enantioselectivity in Carbon-Hydrogen Insertion Reac-
tions of Isobutyl Phenyldiazoacetatea
33, 1797. Padwa, A.; Krumpe, K. E. Tetrahedron 1992, 48,
5385.
(
(
4) Davies, H. M. L. Eur. J. Org. Chem. 1999, 2459.
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Boone, W. P.; Bagheri, V.; Pearson, M. M. J. Am. Chem. Soc.
1
993, 115, 958.
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686.
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996, 118, 8837.
(
(
7
1
a
b
(8) Anada, M.; Hashimoto, S. Tetrahedron Lett. 1998, 39, 79.
(9) Wee, A. G. H. Tetrahedron Lett. 2000, 41, 9025.
(10) Wang, P.; Adams, J. J. Am. Chem. Soc. 1994, 116, 3296.
Reactions were performed as described in Table 1. Yield after of re-
c
moval of catalyst. Analysis on a WHELK-O column using 20%
EtOAc in hexanes. d Reaction performed in pentane.
(
11) Davies, H. M. L.; Hansen, T.; Churchill, M. R. J. Am. Chem.
Soc. 2000, 122, 3063.
(
(
12) Imai, T.; Nichida, S. J. Org. Chem. 1979, 44, 3574.
13) Doyle, M. P.; Zhou, Q.-L.; Simonsen, S. H.; Lynch, V. Synlett
1996, 697.
Ph
Ph
COO
Me
Rh2L4
(14) Doyle, M. P.; Davies, S. B.; Hu, W. Org. Lett. 2000, 2, 1145.
Me
Me
Me
O
(15) Davies, H. M. L.; Hansen, T.; Hopper, D.; Penaro, S. A. J. Am.
Chem. Soc. 1999, 121, 6509.
N2
O
(16) Davies, H. M. L.; Stafford, D. G.; Hansen, T. Org. Lett. 1999,
1, 233.
14
13
(
(
17) Hoppe, I.; Schöllkopf, U. Liebigs Ann. Chem. 1979, 219.
18) Black, T. H.; DuBay, W. J.; Tully, P. S. J. Org. Chem. 1988,
Scheme 4
53, 5922.
(
19) Diastereoisomers were separated, and they were identified by
spectral methods; assignments were based on nOe
experiments.
Article Identifier:
437-2096,E;2001,0,SI,0967,0969,ftx,en;Y02801ST.pdf
1
Acknowledgement
Support for this research from the National Science Foundation and
from the National Institutes of Health (GM-46503) is gratefully
Synlett 2001, SI, 967–969 ISSN 0936-5214 © Thieme Stuttgart · New York