Diastereo- and enantioselective cyclopropanation with chromium fischer carbene complexes: Alkenyl oxazolines as useful achiral and chiral substrates

Article abstract of DOI:10.1021/ja010719m

The cyclopropanation reaction of chromium Fischer carbene complexes with alkenyl oxazolines has been studied in both racemic and enantioselective fashions. The oxazolinyl group acts as both electron-acceptor substituent and chiral auxiliary. Achiral (4,4-

Full text of DOI:10.1021/ja010719m

10494
J. Am. Chem. Soc. 2001, 123, 10494-10501
Diastereo- and Enantioselective Cyclopropanation with Chromium
Fischer Carbene Complexes: Alkenyl Oxazolines as Useful Achiral
and Chiral Substrates
Jose´ Barluenga,*,† Angel L. Sua´rez-Sobrino,† Miguel Toma´s,†
Santiago Garc´ıa-Granda,‡ and Rafael Santiago-Garc´ıa‡
Contribution from the Instituto UniVersitario de Qu´ımica Organometa´lica “Enrique Moles”, and
Departamento de Qu´ımica F´ısica y Anal´ıtica, UniVersidad de OViedo, AVda. Julia´n ClaVer´ıa 8,
33071 OViedo, Spain
ReceiVed March 19, 2001
Abstract: The cyclopropanation reaction of chromium Fischer carbene complexes with alkenyl oxazolines
has been studied in both racemic and enantioselective fashions. The oxazolinyl group acts as both electron-
acceptor substituent and chiral auxiliary. Achiral (4,4-dimethyloxazolin-2-yl)alkenes derived from trans-crotonic
and trans-cinnamic acids 2a,b undergo the cyclopropanation reaction to give 4a-d,g with excellent
diastereoselectivity (trans/cis ratio between 93:7 and >97:3), while those derived from acrylic and metacrylic
acids 2c,d give the cyclopropanes 4e,f,h with much lower selectivity (trans/cis ratio between 68:32 and 83:
17). The homogeneous catalytic hydrogenolysis of 4 leads in a selective manner to 5 or 6, depending on the
nature of the R3 substituent. The removal of the oxazoline moiety is achieved by carboxybenzylation/hydrolysis
and ester reduction, yielding monoprotected 1,4- and 1,3-diols 9 and 11, respectively. The alkenes derived
from enantiopure (S)-valinol and (S)-tert-leucinol 3 led to cyclopropanes trans-12 with high relative and absolute
stereocontrol. Using tert-leucinol as the auxiliary permits attaining total facial stereoselectivity (>98% ee).
Reductive cleavage of the cyclopropane ring and removal of the auxiliary afford the enriched alcohols (3S,4S)-9
and (S)-11. The stereochemical outcome of the cyclopropanation reaction is rationalized by a trans approach
of the s-cis conformer of the alkenyl oxazoline to the carbene complex involving the less hindered face of the
oxazoline auxiliary and the re-face of the carbene complex.
Introduction
poor,4f,6 electron-rich,7 and unfunctionalized 1,3-dienes.8 Sig-
nificantly, studies carried out recently in our laboratory9 showed
for the first time that simple alkenes are capable of undergoing
efficiently the intermolecular cyclopropanation reaction.10,11
The cyclopropanation reaction of electron-poor alkenes
represents one of the first synthetically useful reactions of group
6 Fischer carbene complexes since their discovery by E. O.
Fischer.1 This reaction has been thoroughly studied not only
for theoretical purposes, but more importantly also as a powerful
method to access donor-acceptor cyclopropanes,2 compounds
that have gained attention because of their high potential to serve
as versatile intermediates.3 The cyclopropanation reaction was
first reported for electron-poor1,4 and, to a much lesser extent,
electron-rich alkenes,5 and later it was extended to electron-
After 30 years since its discovery, it is well recognized that
the stereochemical control is the major limitation of the cy-
clopropanation reaction using Fischer-type carbene complexes.
Thus, the cis/trans diastereoselectivity is generally lows
(5) (a) Fischer, E. O.; Do¨tz, K. H. Chem. Ber. 1972, 105, 3966. (b) Dorrer,
B.; Fischer, E. O.; Kalbfus, W. J. Organomet. Chem. 1974, 81, C20. (c)
Murray, C. K.;. Yang, D. C.; Wulff, W. D. J. Am. Chem. Soc. 1990, 112,
5660. (d) Review: Wulff, W. D.; Yang, D. C.; Murray, C. K. Pure Appl.
Chem. 1988, 60, 137.
(6) (a) Buchert, M.; Reissig, H.-U. Tetrahedron Lett. 1988, 29, 2319.
(b) Buchert, M.; Reissig, H.-U. Chem. Ber. 1992, 125, 2723. (c) Buchert,
M.; Hoffmann, M.; Reissig, H.-U. Chem. Ber. 1995, 128, 605. (d) Barluenga,
J.; Toma´s, M.; Sua´rez-Sobrino A. L. Synthesis 2000, 935.
* Corresponding author. Telephone and fax: (34) 98 5103450. E-mail:
barluenga@sauron.quimica.uniovi.es.
† Instituto Universitario de Qu´ımica Organometa´lica “Enrique Moles”.
‡ Departamento de Qu´ımica F´ısica y Anal´ıtica (X-ray service).
(1) (a) Fischer, E. O.; Do¨tz, K. H. Chem. Ber. 1970, 103, 1273. (b) Do¨tz,
K. H.; Fischer, E. O. Chem. Ber. 1972, 105, 1356.
(7) Wulff, W. D.; Yang, D. C.; Murray, C. K. J. Am. Chem. Soc. 1988,
110, 2653.
(2) Reviews: (a) Brookhart, M.; Studebaker, W. B. Chem. ReV. 1987,
87, 7, 411. (b) Reissig H.-U. In Organometallics in Organic Synthesis;
Werner, H.; Erker, G., Eds.; Springer: Berlin, 1989; Vol. 2, pp 311-322.
(c) Doyle, M. P. In ComprehensiVe Organometallic Chemistry II; Abel, E.
W., Stone, F. G. A., Wilkinson, G., Eds; Pergamon: Oxford, 1995; Vol.
12, pp 387-420. (d) Harvey, D. F.; Sigano, D. M. Chem. ReV. 1996, 96,
271.
(8) (a) Harvey, D. F.; Lund, K. P. J. Am. Chem. Soc. 1991, 113, 8916.
(b) Merlic, C. A.; Bendorf, H. D. Tetrahedron Lett. 1994, 35, 9529.
(9) (a) Barluenga, J.; Ferna´ndez-Acebes, A.; Trabanco, A. A.; Flo´rez, J.
J. Am. Chem. Soc. 1997, 119, 7591. (b) Barluenga, J.; Lo´pez, S.; Trabanco,
A. A.; Ferna´ndez-Acebes, A.; Flo´rez, J. J. Am. Chem. Soc. 2000, 122, 8145.
(10) Selected intramolecular cyclopropanations: (a) Barluenga, J.; Mont-
serrat, J. M.; Flo´rez, J. J. Chem. Soc., Chem. Commun. 1993, 1068. (b)
So¨derberg, B. C.; Hegedus, L. S. Organometallics 1990, 9, 3113.
(11) Selected cyclopropanation reactions with non-heteroatom-stabilized
group 6 carbene complexes: (a) Casey, C. P.; Albin, L. D.; Burkhardt, T.
J. J. Am. Chem. Soc. 1977, 99, 2533. (b) Harvey, D. F.; Brown, M. F. J.
Am. Chem. Soc. 1990, 112, 7806. (c) Rudler, H.; Audouin, M.; Parlier, A.;
Martin-Vaca, B.; Goumont, R.; Durand-Re´ville, T.; Vaissermann, J. J. Am.
Chem. Soc. 1996, 118, 12045.
(3) (a) Reissig, H.-U. Top. Curr. Chem. 1988, 144, 73. (b) Ullman, A.;
Gruner, M.; Reissig, H.-U. Chem. Eur. J. 1999, 5, 187.
(4) (a) Wienand, A.; Reissig, H.-U. Tetrahedron Lett. 1988, 29, 2315.
(b) Herndon, J. W.; Tumer, S. U. Tetrahedron Lett. 1989, 30, 4771. (c)
Wienand, A.; Reissig, H.-U. Organometallics 1990, 9, 3133. (d) Harvey,
D. F.; Brown, M. F. Tetrahedron Lett. 1990, 31, 2529. (e) Wienand, A.;
Reissig, H.-U. Chem. Ber. 1991, 124, 957. (f) Herndon, J. W.; Tumer, S.
U. J. Org. Chem. 1991, 56, 286.
10.1021/ja010719m CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/05/2001

Oxazolines for EnantioselectiVe Cyclopropanation
J. Am. Chem. Soc., Vol. 123, No. 43, 2001 10495
Scheme 1. Cyclopropanation of Achiral Alkenyl Oxazolines
with Chromium Carbene Complexes
Figure 1. Structures of carbene complexes and alkenyl oxazolines used.
frequently close to 1:1sexcept when either alkenyl carbene
complexes or 1,3-diene based substrates are employed. As an
isolated example, we reported excellent diastereoselection in
the cyclopropanation of alkenylimines (1-azadienes) by pen-
tacarbonyl[phenyl(methoxy)]carbenechromium complex, in which
the nitrogen functionality must exert some influence on the
stereochemical course.12 Significantly, no enantioselective cy-
clopropanation reactions using Fischer-type carbene complexes
have been hitherto described,13,14 although E. O. Fischer reported
in 1973 the use of a chiral phosphine ligand-containing chro-
mium carbene complex to demonstrate that no free carbene
species were involved in the cyclopropanation reaction.15 The
use of chiral-at-metal complexes in enantioselective cyclopro-
panation reactions has been reported by Brookhart et al. for
non-heteroatom-stabilized electrophilic iron carbene com-
plexes.16
Our observation that alkenes with an imine functionality are
cyclopropanated with high stereochemical control (see above)12
along with the fact that readily accessible, chiral oxazolines are
well-known as efficient auxiliaries in enantioselective synthe-
sis17,18 prompted us to investigate the reaction of simple
chromium carbene complexes with various achiral and enan-
tiopure alkenyl oxazolines. We describe herein the results of
this study which allows for the effective cyclopropanation with
Fischer carbene complexes of chromium in a diastereo and
enantioselective fashion. The selective hydrogenolysis of the
resulting cyclopropane ring and the subsequent removal of the
chiral auxiliary are also reported.
Table 1. Racemic Cyclopropanes 4 Prepared from Carbene
Complexes 1 and Oxazolines 2
entry
R1
Ph
n-Bu Me Me
Ph Me Ph
n-Bu Me Ph
R2 R3 R4 product yield (%)a trans-4/cis-4b
1
2
3
4
5
6
7
8
Me Me
H
H
4a
4b
4c
4d
4e
4f
89
85
92
90
84
82
88
87
>97:<3
93:7
H
H
H
>97:<3
>97:<3
68:32
Ph
Ph
Ph
Ph
Me
Me
i-Pr Me
i-Pr
H
H
Me
H
H
83:17
>97:<3
74:26
4g
4h
H
a Isolated yields after column chromatography (silica gel, hexanes/
1
ethyl acetate, 3:1). b Determined by H NMR.
reaction went to completion upon heating at 60 °C for 14 h
affording cleanly the [2 + 1] cycloadduct 4a after demetalation
of the reaction mixture (air, sunlight). The crude product was
subjected to column chromatography to furnish pure cyclopro-
pane trans-4a in 89% yield as the sole diastereoisomer (1H
NMR, 300 MHz) (entry 1). Similarly, the oxazoline 2a gave,
on reaction with butyl carbene complex 1b, the expected
cycloadduct trans-4b, slightly contaminated with cis-4b (trans:
cis ) 93:7) (entry 2). The cyclopropanation of the styryl
oxazoline 2b with complexes 1a,b required heating at 100 °C
(toluene, 14 h) and yielded the cycloadducts trans-4c,d with
complete diastereoselectivity (entries 3,4). On the contrary,
lower selectivity was found when the alkenyl oxazoline lacks a
Câ-substituent, as in the reaction of 1a with alkenyl oxazolines
2c,d (trans/cis ) 2.1 and 5.0 for 4e and 4f, respectively) (entries
5,6). Increasing the bulkiness of the alkoxy substituent of the
carbene ligand (1c, R2 ) i-Pr) results in some improvement of
the selectivity. While the reaction of 1c and crotonyl oxazoline
2a gave only trans-4g as expected (entry 7 vs entry 1), the
diastereomeric ratio for the acrylic derivative 2c increased from
2.1 (entry 5) to 2.8 (entry 8). It is noticeable that the reactions
were in all cases very clean and the yields very high (ranging
from 82 to 92%).
The present study has been undertaken using (i) pentacar-
bonyl[phenyl(alkoxy)]- and pentacarbonyl[butyl(alkoxy)]carbene
chromium complexes 1a-c, (ii) achiral oxazolines 2a-d,
derived from 2-amino-2-methyl-1-propanol and (E)-2-butenoic
(2a), (E)-3-phenylpropenoic (2b), propenoic (2c), and 2-meth-
ylpropenoic (2d) acids, and (iii) enantiopure oxazolines 3a-c
derived from (S)-valinol (R5 ) i-Pr) and (E)-2-butenoic (3a)
and (E)-3-phenylpropenoic (3b) acids and from (S)-tert-leucinol
and (E)-2-butenoic acid (3c) (Figure 1).
Results and Discussion
Synthesis and Ring-Opening of Racemic Cyclopropanes.
The reaction of the chromium carbene complexes 1 and achiral
alkenyl oxazolines 2 was first studied (Scheme 1, Table 1). We
observed that no reaction occurred between the phenyl carbene
complex 1a (R1dPh; R2 ) Me) and the alkenyl oxazoline 2a
(R3 ) Me; R4dH) in THF at room temperature. However, the
(12) Barluenga, J.; Toma´s, M.; Lo´pez-Pelegr´ın, J. A.; Rubio, E. J. Chem.
Soc., Chem. Commun. 1995, 665.
(13) Wulff, W. D. Organometallics 1998, 17, 3116.
(14) Enantioselective cyclopropanation with alkyl diazoacetates/metal
complexes: (a) Doyle, M. P.; Forbes, D. C. Chem. ReV. 1998, 98, 911. (b)
Davies, H. M. L.; Boebel, T. A. Tetrahedron Lett. 2000, 41, 8189.
(15) Cooke, M. D.; Fischer, E. O. J. Organomet. Chem 1973, 56, 279.
(16) Brookhart, M.; Liu, Y.; Goldman, E. W.; Timmers, D. A.; Williams,
G. D. J. Am. Chem. Soc. 1991, 113, 927.
(17) Review: Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297.
(18) We have recently described the [3 + 2] cyclization of achiral alkenyl
oxazolines to alkenyl carbene complexes.6d
All attempts to transform the auxiliary oxazoline moiety into
carbonyl or carboxylic acid derivatives17 without affecting the
cyclopropane framework were unsuccessful; instead, cleavage
of the ring occurred under the reaction conditions tested. This
fact is not unexpected, due to the lability of the C1-C2 bond
of cyclopropanes having both donor and acceptor substituents.3
At this point we decided to investigate a two-step alternative

10496 J. Am. Chem. Soc., Vol. 123, No. 43, 2001
Barluenga et al.
Scheme 2. Hydrogenolysis of Racemic Cyclopropanes 4 and Hydrolysis-Reduction of the Oxazoline Moietya
a (i) H2/Pd (1 atm); Et3N-THF, 25°C. (ii) Cbz-Cl, Na2CO3, CH2Cl2, 25° C. (iii) DIBAL-H, toluene, 25°C. (iv) LiAlH4, THF, 25°C.
Scheme 3. Cyclopropanation of Enantiopure Alkenyl
Oxazolines with Chromium Carbene Complexes
route, (i) hydrogenolysis of the cyclopropane ring and (ii)
hydrolysis-reduction of the oxazoline moiety (Scheme 2). The
hydrogenation of cyclopropanes 4a,g (R3 ) Me) [H2 (1 atm)/
Pd-C/Et3N-THF] at room temperature resulted in the forma-
tion of 5a,g in 90-93% yield (via a).19 Interestingly, the
hydrogenolysis reaction was found to take place not only in a
regioselective manner, as only the C1-C2 bond of the cyclo-
propane ring suffered cleavage, but also with complete stereo-
selectivity. Moreover, the stereochemical analysis of 5 (vide
infra) reveals that the hydrogenation of C1 takes place with
inversion of configuration. This result is of great significance
since previous hydrogenolysis reactions of siloxy-methoxycar-
bonyl-substituted cyclopropanes have been reported by Reissig
et al. to take place with low stereoselectivity (diastereoisomeric
ratios from 1:1 to 2:1).4c,19 On the contrary, when a phenyl group
is placed on C3, as for 4c (R3dPh), a reversal of the sense of
the regiocontrol was observed, leading exclusively to 6 (95%
yield) by reductive breaking of the C2-C3 bond (via b). The
Table 2. Enantiopure Cyclopropanes 12 and 13 from Carbene
resulting oxazolines 5 and 6 were treated with benzyl chloro-
Complexes 1 and Oxazolines 3
formate in the presence of aqueous sodium carbonate,20 afford-
yield trans-12/ trans-12/
ing the carbamates 7 and 8. Without purification, these
entry R1
R2 R3 R5 products (%)a cis-12b trans-13b
compounds were reduced with DIBAL-H and LAH, respec-
tively, to produce the corresponding racemic methoxybutanols
9a,b (73-76% overall yield from 5a,g) and 11 (79% overall
yield from 6). No traces of the syn-diastereoisomer 10 were
detected (1H NMR, 300 MHz) in the former case.
Synthesis and Ring-Opening of Enantiopure Cyclopro-
panes. The readily accessible (S)-isopropyloxazoline derivatives
3a,b were first selected as the model enantiopure partners for
the enantioselective cyclopropanation reaction (Scheme 3; Table
2, entries 1-4). Compared with the case of achiral oxazolines
2, no noticeable changes when using 3 were observed in terms
of reaction conditions (THF/60 °C for oxazolines 3a; toluene/
100 °C for oxazoline 3b) and yields (86-94%). The four
diastereoisomers that might be formedstrans-12 and cis-12,
1
2
3
4
5
6
Ph
Ph
Me Me i-Pr 12a/13a 89
Me Ph i-Pr 12b/13b 94
83:17
84:16c
58:42
90:10
85:15c
94:6
92:8
>99:<1
85:15
95:5
>99:<1
>99:<1
n-Bu Me Ph i-Pr 12c/13c
90
Ph
Ph
Ph
i-Pr Me i-Pr 12d/13d 86
Me Me t-Bu 12e/13e
i-Pr Me t-Bu 12f/13f
87
86
a Isolated yields after column chromatography (silica gel, hexanes/
ethyl acetate 3:1). b Determined by GC-MS. c >99:<1 After crystal-
lization from pentane.
trans-13 and cis-13sare shown in Scheme 3. Gratifyingly, very
high face selectivity was achieved in the formation of the trans
cycloadduct (in most cases >90% de in favor of trans-12 was
observed). On the contrary, the cis/trans selectivity of the
cyclopropanation was not as high as that found for achiral
oxazolines 2 (trans-12/cis-12 ) 1.4-9.0). For instance, the
cyclopropanation of alkenyl oxazolines 3a,b (R5 ) i-Pr) with
carbene complex 1a (entries 1,2) took place with acceptable
cis/trans stereoselectivity (trans-12/cis-12 ≈ 5) and very high
facial selectivity (84% de for trans-12a and >98% de for trans-
(19) On the basis of the work by Bru¨ckner and Reissig for closely related
substrates, triethylamine-poisoned catalyst was used to avoid further
hydrogenolysis of the benzylic C-O bond. See: Bru¨ckner, C.; Reissig,
H.-U. Chem. Ber. 1987, 120, 617.
(20) Kouklovsky, C.; Pouilhe`s, A.; Langlois, Y. J. Am. Chem. Soc. 1990,
112, 6672.

Oxazolines for EnantioselectiVe Cyclopropanation
J. Am. Chem. Soc., Vol. 123, No. 43, 2001 10497
Scheme 4. Hydrogenolysis via Cleavage of the C1-C2
Bond of Enantiopure Cyclopropanes and
Scheme 5. Hydrogenolysis via Cleavage of the C2-C3
Bond of Enantiopure Cyclopropane trans-12b and
Hydrolysis-Reduction of the Oxazoline Moietya
Hydrolysis-Reduction of the Oxazoline Moietya
a (i) H2/Pd (1 atm); Et3N-THF, 25°C. (ii) Cbz-Cl, Na2CO3, CH2Cl2.
(iii) LiAlH4, THF, 25°C.
diastereoisomers wherein compounds 14 and 15, arising from
trans-12 and cis-12, respectively, were largely predominant.
Then, the resulting mixture was subjected to reductive removal
of the oxazoline auxiliary to furnish (3S,4S)-9 and (3S,4R)-10,
as the major stereoisomers. In turn, the minor stereoisomers
(3R,4R)-9 and (3R,4S)-10 (not shown) would originate from
trans-13 and cis-13, respectively. The HPLC analyses revealed
that the major isomers (3S,4S)-9a,b had produced with an
enantiomeric purity of up to 99% (Table 3) and confirmed the
excellent face selectivity for the trans-cyclopropane adducts (see
also trans-12/trans-13 ratio in Table 2), particularly for alkenyl
oxazolines derived from tert-leucinol [see ee’s for (3S,4S)-9 in
Table 3; entries: 3 vs 1 and 4 vs 2]. In Table 3 is also displayed
the ee values of the minor isomers (3S,4R)-10a,b, which actually
express the face selectivity for the cis-cyclopropane adducts.
In this case, low enantioselectivity was observed when starting
from the (S)-valinol oxazoline 3a (40-46% ee; entries 1,2),
while high ee values are reached if the tert-leucinol oxazoline
3c is used (84-94%; entries 3,4). The little discrepancy found
in the ratio values for trans-12/cis-12 (see Table 2) vs (3S,4S)-
9/(3S,4R)-10 (see Table 3) reflects again that the hydrogenolysis
of the cyclopropane ring takes place with very high, but not
complete, stereoselectivity. It can be deduced from Tables 2
and 3 that the diastereoselectivity of the hydrogenolysis of
cyclopropanes 12 ranges from 85 to 95%. Moreover, the 14/15
ratio values (1H NMR, 300 MHz) match well those found for
(3S,4S)-9/(3S,4R)-10 (HPLC analysis of the carbamates derived
from phenylisocyanate).
Finally, hydrogenolysis of the C2-C3 bond of the single
cycloadduct trans-12b was performed under standard conditions
leading to the open-chain derivative 16 (96% yield) as a single
isomer on the basis of its 300 MHz 1H NMR spectrum (Scheme
5). The conversion of the oxazoline moiety of 16 into the alcohol
(S)-11 was efficiently accomplished by formation of the
carbamate (CbzCl, Na2CO3) and by hydride reduction (LAH).
The monoprotected 1,3-butanediol derivative (S)-11 was thus
obtained in 74% yield from 16 and 97% ee (HPLC, Chiracel
OD-H column, hexane/ethanol, 150:1).
Structural Analysis. The assignment of the relative stereo-
chemistry for single racemic and enantiopure cyclopropanes
(trans-4 and trans-12b,e) was based on 2D-NOESY NMR ex-
periments. Crystals of the adduct anti-14e were growth from
pentane and the X-ray analysis was performed (Figure 2),21 thus
allowing for its absolute stereochemistry to be established. The
full structure of all compounds is drawn in accordance with
these analyses and on the basis that the cyclopropane carbon
a (i) H2/Pd (1 atm); Et3N-THF, 25°C. (ii) Cbz-Cl, Na2CO3, CH2Cl2.
(iii) DIBAL-H, toluene, 25°C.
12b). Unfortunately, the selectivity dropped dramatically for
the pentacarbonyl[butyl(methoxy)]carbene chromium complex
1b, as shown in the formation of 12c (entry 3; trans-12c/cis-
12c ) 1.4; 70% de for trans-12c). Therefore, further efforts
were made to improve the relative and absolute stereocontrol.
In this context, slightly superior results were reached when the
isopropoxycarbene 1c (R2 ) i-Pr) was employed in place of
the methoxy counterpart 1a (R2 ) Me) (compare entries 1 and
4). At this point, we turned our attention to the alkenyl oxazoline
3c that contains a bulkier group (R5 ) t-Bu; entries 5,6). First,
the reaction of 1a with 3c took place under the standard reaction
conditions and with comparable yield, allowing for almost total
absolute stereocontrol, although no significant improvement of
the relative stereocontrol could be attained (compare entries 1
and 5). As expected, combining both structural modifications
on the carbene and on the oxazoline partners provided the best
overall stereoselectivity. This event is illustrated in entry 6,
which shows that the carbene complex 1c and the alkenyl
oxazoline 3c formed the cyclopropane 12f in good chemical
yield (86%) and with excellent relative and absolute stereocon-
trol (trans-12f/cis-12f ) 16; >98% de for trans-12f).
The diastereoisomers trans-12e (R3 ) Me) and trans-12b
(R3dPh) were efficiently isolated as single isomers (trans/cis
) > 99:1) by recrystallization from pentane (>85% recovering
material) and afterward used as model cyclopropanes for further
elaboration into the chiral, nonracemic alcohols 9 and 11
(Schemes 4 and 5, respectively).
When trans-12e was subjected to hydrogenolysis [H2 (1 atm)/
Pd-C/Et3N-THF, 25 °C], regioselective cleavage of the C1-
C2 bond occurred to give 14e (93% yield) as a 93:7 anti:syn
mixture (Scheme 4). Moreover, the isolation of anti-14e in pure
form was readily achieved by recrystallization from pentane.
The final elaboration of pure 14e into (3S,4S)-9a (99% ee) was
accomplished in 71% overall yield by successive treatment with
CbzCl/Na2CO3 and DIBAL-H.
(21) Crystal data of compound 14e C18H27NO2, Mr ) 289.41, Monoclinic,
space group P21, a ) 7.407(4) Å, b ) 12.392(3) Å, c ) 9.432(6) Å, â )
102.58(2)°, V ) 844.9(7) Å3, Z ) 2, Dx ) 1.138 Mg/m3, Mo KR radiation
(graphite crystal Monochromator, λ ) 0.071073 Å), µ ) 0.07 mm-1, F(000)
) 316, T ) 200(2) K. Final conventional R ) 0.038, ωR2 ) 0.082 and S
) 1.033, for 1088 “observed” reflections and 261 variables.
The reductive cleavage of the C1-C2 bond was also
performed on the diastereoisomeric cyclopropane mixtures
12/13a,d,e,f (R3 ) Me) (Scheme 4, Table 3). First, the
hydrogenolysis reaction afforded mixtures consisting of four

10498 J. Am. Chem. Soc., Vol. 123, No. 43, 2001
Barluenga et al.
Table 3. Enantiopure Alcohols 9 and 10 from Cyclopropanes 12 and 13
(3S,4S)-9/
ee (%)
ee (%)
entry
cyclopropanes
R2
R5
products
yielda,b (%)
(3S,4R)-10c,d
(3S,4S)-9d
(3S,4R)-10d
1
2
3
4
12a/13a
12d/13d
12e/13e
12f/13f
Me
i-Pr
Me
i-Pr
i-Pr
i-Pr
t-Bu
t-Bu
9a/10a
9b/10b
9a/10a
9b/10b
70
71
71
75
77:23
88:12
78:22
91:9
84
90
99
98
46
40
94
84
a Overall yield from 14/15. b Isolated yields after column chromatography (silica gel, hexanes/ethyl acetate, 3:1). c Determined for oxazolines
1
14/15 by H NMR. d Determined by HPLC of the phenylcarbamate derivatives (Chiracel OD-H column hexane/isopropyl alcohol 3:1).
The extension of the reaction to chiral nonracemic alkenyl
oxazolines allowed us to develop the first enantioselective
cyclopropanation with heteroatom-stabilized group 6 Fischer
carbene complexes.24 The asymmetric induction for the major
trans-diastereoisomer is not only very high, but it can also be
increased in general to more than 98% by choosing properly
the carbene alkoxy group and the oxazoline substituent. In this
case, cis/trans diastereomeric ratios up to 88% were also
reached. The removal of the chiral auxiliary cannot be achieved
on the cyclopropane itself, but it can be accomplished if the
cyclopropanes are previously subjected to hydrogenation. It is
worth noting that the cyclopropanes undergo stereospecific
Figure 2. X-Ray crystal structure of compound 14e.
reductive cleavage with inversion of configuration.
center not involved in the hydrogenolysis reaction does not
epimerize along the successive reactions.
Experimental Section
General. All reactions involving air-sensitive compounds were
carried out under a N2 atmosphere (99.99%). All glassware was oven-
dried (120 °C), evacuated, and purged with nitrogen. All common
reagents and solvents were obtained from commercial suppliers and
used without any further purification unless otherwise indicated. Fischer
carbene complexes were prepared following described procedures.
Solvents were dried by standard methods. Flash column chromatography
was carried out on silica gel 60, 230-240 mesh. High-performance
liquid chromatography was carried out using a Shimadzu LC-10 and a
Waters LC Module I Plus chromatograph, each equipped with a vis-
UV Diode-Array detectors; Chiralcel OD-H was employed as chiral
column. Enantiomeric excess values were either determined by HPLC
of the isolated alcohol or its phenylcarbamate derivative. NMR
experiments were carried out on a Bruker AC-300 spectrometer.1H
NMR spectra were recorded in CDCl3 at 300.08 MHz at 20 °C with
tetramethylsilane (δ ) 0.0) as the internal standard.13C NMR spectra
Stereochemical Results. The reaction course outlined in
Figure 3 is proposed on the basis of (i) the accepted mechanism
for the cyclopropanation reaction of heteroatom-stabilized
carbene complexes and electron-withdrawing alkenes22 and (ii)
the relative and absolute stereochemistry of all the cycloadducts.
The s-cis alkenyl oxazoline23 might approach the re-face or the
si-face of the metal-carbene double bond. Moreover, this
approach can take place according to a cis- or trans-arrangement
(in reference to oxazolinyl and alkoxy substituents). Thus, the
trans-approach of the s-cis alkenyl oxazoline to the re-face of
the carbene moiety (pathway A) would form the allyl-type trans-
metallacyclobutane I, which would yield, upon reductive
elimination, the major cyclopropane trans-12 first and, at the
latest stage, the final alcohol (3S,4S)-9. On the other hand, the
cis-metallacyclobutane species II, precursor of cis-12 and
(3S,4R)-10, would arise from the cis-approach of the alkenyl
oxazoline to the si-face of the carbene moiety (pathway B). The
preference for the trans-metallacyclobutane species seems to
be a consequence of steric interaction between the alkoxy and
oxazolinyl groups. Finally, the trans-approach of the s-cis
alkenyl oxazoline to the si-face of the carbene moiety (pathway
C) would generate the trans-metallacyclobutane species III,
precursor of trans-13 and (3R,4R)-9. In the same way, the cis-
approach of the s-cis alkenyl oxazoline to the re-face of the
carbene moiety would form the cis-metallacyclobutane species
IV (pathway D) which is the precursor of the minor stereoiso-
mers cis-13 and (3R,4S)-10. These latter attacks (pathways C,
and D) appear to be much less favorable due to the steric
interaction between the R5 group of the oxazoline auxiliary and
the tetracarbonyl-metal fragment.
1
were recorded in CDCl3 at 75.46 MHz at 20 °C. H NMR splitting
pattern abbreviations are: s, singlet; d, doublet; t, triplet; q, quartet;
m, multiplet. 13C NMR multiplicities were determined by DEPT,
abbreviations are: q, CH3; t, CH2; d, CH; s, quaternary carbons. NOESY
experiments were carried out on a Bruker AMX-400 spectrometer.
Standard pulse sequences were employed for the DEPT experiments.
High-resolution mass spectra (HRMS) were obtained with a Finnigan
Mat95 Mass Spectrometer, electron impact techniques (70 eV) were
employed. Melting points were determined on a Bu¨chi-Tottoli
apparatus and are uncorrected. For optical rotations a Perkin-Elmer
241 polarimeter was employed; values were determined using the
sodium lamp, and the concentration was reported in g/100 mL.
Elemental analyses were carried out with a Perkin-Elmer 240 B
microanalyzer.
Synthesis of Cyclopropanes 4, 12, and 13. General Procedure.
A mixture of the carbene complex 1 (1.5 mmol) and alkenyl oxazolines
2 or 3 (1.5 mmol) in THF (toluene for 2b and 3b) (20 mL) was heated
(23) The requirement of the s-cis conformation for the alkene is well-
documented in the literature. Thus, Wienand and Reissig have demonstrated
that R,â-unsaturated lactones that cannot reach a cis conformation between
the CdC and CdO bonds fail to undergo cyclopropanation with chromium
carbene complexes.4c In a similar way, only dienes with a readily accessible
s-cis conformation can participate in this reaction, as reported by Harvey
and Lund.8a
(24) Alkenoic acid esters derived from chiral alcohols are not capable
of achieving the enantioselective cyclopropanation. In fact, we have
experienced that the carbene complex 1a does not react with (()-
phenylcyclohexyl acrylate at temperatures up to 120 °C.
Conclusions
The results reported herein demonstrate that alkenyl oxazo-
lines are excellent electron-poor alkene surrogates for the
cyclopropanation reaction with group 6 Fischer carbene com-
plexes. Thus, the achiral systems are smoothly cyclopropanated
in very good yield and with unusually high diastereoselectivity.
(22) Casey, C. P.; Cesa, M. Organometallics 1982, 1, 87.

Oxazolines for EnantioselectiVe Cyclopropanation
J. Am. Chem. Soc., Vol. 123, No. 43, 2001 10499
Figure 3. Proposed stereochemical and mechanistic aspects for the reaction course.
at 60 °C (100 °C for 2b and 3b) for 14 h. Then the solvent was removed
under vacuum, and the crude product was dissolved in a mixture of
EtOAc/hexane (1:1) and air-oxidized in an open flask under sunlight
or lamp light (10-12 h). The solution was then filtered over Celite,
and the filtrate was concentrated under vacuum. The resulting crude
product was purified by column chromatography (silica gel, hexanes/
EtOAc, 3:1).
10.0, 6.3 Hz, 1H), 1.1 (s, 3H), 0.7 (s, 3H); 13C NMR: δ ) 162.5 (s),
139.0 (s), 129.1(d, 2C), 127.5 (d), 127.3 (d, 2C), 78.8 (t), 69.0(s), 66.3-
(s), 54.5 (q), 27.9 (q), 27.6 (q), 24.0 (d), 15.0 (t); HRMS m/z calcd for
C15H19NO2 245.1416; found 246.1417. Anal. Calcd for C15H19NO2: C
73.44, H 7.81, N 5.71. Found: C 73.23, H 7.93, N 5.59.
trans-2-(4,4-Dimethyl-2-oxazolin-2-yl)-1-methoxy-2-methyl-1-phen-
ylcyclopropane (trans-4f): obtained as a mixture of diastereoisomers
(trans-4f/cis-4f, 83:17); oil; yield ) 82%; 1H NMR: δ ) 7.4-7.1 (m,
5 H), 3.5 (s, 2H), 3.1 (s, 3H), 2.0 (d, J ) 6.1 Hz, 1H), 1.6 (s, 3H), 1.1
(s, 3H), 1.0 (d, J ) 6.1 Hz, 1H), 0.6 (s, 3H); 13C NMR: δ ) 165.0 (s),
135.9 (s), 128.7 (d, 2C), 127.0 (d, 3C), 78.3 (t), 70.1 (s), 65.7 (s), 54.3
(q), 27.5 (q), 27.4 (s), 27.0 (q), 20.3 (t), 14.9 (q); HRMS m/z calcd for
C16H21NO2 259.1572; found 259.1582. Anal. Calcd for C16H21NO2: C
74.10, H 8.16, N 5.40. Found: C 74.23, H 8.01, N 5.56.
trans,trans-2-(4,4-Dimethyl-2-oxazolin-2-yl)-1-methoxy-3-methyl-
1-phenylcyclopropane (trans-4a): obtained as a single diastereoisomer;
1
oil; yield ) 89%; H NMR: δ ) 7.4-7.2 (m, 5 H), 3.6 (d, J ) 7.9
Hz, 1H), 3.5 (d, J ) 7.9 Hz, 1H), 3.1 (s, 3H), 2.1 (m, 1H), 1.7 (d, J )
7.0 Hz, 1H), 1.4 (d, J ) 8.4 Hz, 3H), 1.1 (s, 3H), 0.6 (s, 3H); 13C
NMR: δ ) 162.9 (s), 136.0 (s), 129.5 (d, 2C), 127.7 (d, 3C), 78.6 (t),
72.0 (s), 66.2 (s), 55.0 (q), 29.5(d), 28.0 (q), 27.6 (q), 23.0 (d), 11.2
(q); HRMS m/z calcd for C15H18NO2 [M - CH3]+ 244.1337; found
244.1338. Anal. Calcd for C16H21NO2: C 74.10, H 8.16, N 5.40.
Found: C 74.29, H 8.05, N 5.59.
trans,trans-2-(4,4-Dimethyl-2-oxazolin-2-yl)-1-isopropoxy-3-meth-
yl-1-phenylcyclopropane (trans-4g): obtained as a single diastereo-
1
isomer; oil; yield ) 88%; H NMR: δ ) 7.4-7.1 (m, 5 H), 3.7 (m,
trans,trans-1-Butyl-2-(4,4-dimethyl-2-oxazolin-2-yl)-1-methoxy-
3-methylclopropane(trans-4b): obtained as a mixture of diastereo-
isomers (trans-4b/cis-4b, 93:7); oil; yield ) 85%; 1H NMR: δ ) 3.9
(d, J ) 7.8 Hz, 1H), 3.8 (d, J ) 7.8 Hz, 1H), 3.1 (s, 3H), 2.0 (m, 2H),
1.4-1.1 (m, 6H), 1.2 (s, 3H), 1.1 (s, 3H), 1.0 (d, J ) 5.9 Hz, 3H), 0.9
(t, J ) 7.0 Hz, 3H); 13C NMR: δ ) 163.9 (s), 78.9 (t), 70.2 (s), 66.3
(s), 53.9 (q), 28.8 (d), 28.7 (t), 28.1 (q), 27.9 (q), 27.3 (t), 24.9 (d),
22.5 (t), 13.8 (q), 13.0 (q); HRMS m/z calcd for C13H22NO2 [M -
CH3]+ 224.1650; found 224.1648. Anal. Calcd for C14H25NO2: C 70.25,
H 10.53, N 5.85. Found: C 70.39, H 10.36, N 5.72.
1H), 3.6 (d, J ) 7.0 Hz, 1H), 3.4 (d, J ) 7.0 Hz, 1H), 2.0 (m, 1H), 1.7
(d, J ) 7.0 Hz, 1H), 1.4 (d, J ) 6.4 Hz, 3H), 1.1 (s, 3H), 1.0 (d, J )
6.1 Hz, 6H), 0.7 (s, 3H); 13C NMR: δ ) 163.2 (s), 137.7(s), 129.5 (d,
2C), 127.4 (d, 3C), 78.4 (t), 70.5 (s), 69.4 (d), 66.0 (s), 29.1 (d), 27.9
(q), 27.4 (q), 23.2 (q), 22.9 (q), 22.5 (d), 12.0 (q); HRMS m/z calcd
for C15H18NO2 [M-C3H7]+ 244.1337; found 244.1337; Anal. Calcd
for C18H25NO2: C 75.22, H 8.77, N 4.87. Found: C 75.20, H 8.70, N
4.95.
trans-trans-2-(4,4-Dimethyl-2-oxazolin-2-yl)-1-isopropoxy-1-phen-
ylcyclopropane (trans-4h): obtained as a mixture of diastereoisomers
1
trans,trans-2-(4,4-Dimethyl-2-oxazolin-2-yl)-1-methoxy-1,3-diphen-
ylcyclopropane (trans-4c): obtained as a single diastereoisomer, white
solid, mp 81-83 °C; yield ) 92%; 1H NMR: δ ) 7.6-7.2 (m, 10 H),
3.7 (d, J ) 7.9 Hz, 1H), 3.6 (d, J ) 7.9 Hz, 1H), 3.3 (d, J ) 8.4 Hz,
(trans-4h/cis-4h, 74:26); oil; yield ) 87%; H NMR: δ ) 7.5-7.1
(m, 5 H), 3.7 (m, 1H), 3.5 (d, J ) 8.3 Hz, 1H), 3.4 (d, J ) 8.3 Hz,
1H), 2.1 (dd, J ) 10.0, 7.0 Hz, 1H), 1.8 (dd, J ) 7.0, 6.1 Hz, 1H), 1.4
(dd, J ) 10.0, 6.1 Hz, 1H), 1.1 (s, 6H), 1.0 (d, J ) 6.1 Hz, 3H), 0.9
(d, J ) 6.1 Hz, 3H); 13C NMR: δ ) 162.8 (s), 136.5 (s), 129.3 (d,
2C), 127.0 (d, 3C), 78.7 (t), 69.5 (d), 66.1 (s), 65.9 (s), 28.5 (q), 28.1
(q), 23.2 (d), 23.0 (q), 22.5 (q), 16.7 (t); HRMS m/z calcd for C17H23-
NO2 273.1729; found 273.1725. Anal. Calcd for C17H23NO2: C 74.69,
H 8.48, N 5.12. Found: C 74.81, H 8.55, N 5.20.
1H), 2.8 (s, 3H), 2.7 (d, J ) 8.4 Hz, 1H), 1.2 (s, 3H), 0.8 (s, 3H); 13
C
NMR: δ ) 162.0 (s), 135.6 (s), 135.1 (s), 129.6 (d), 128,2 (d), 128.0
(d), 127.9 (d), 127.8 (d), 126.3 (d), 78.9 (t), 73.1 (s), 66.5 (s), 54.6 (q),
33.0 (d), 29,1 (d), 28.0 (q), 27.6 (q); HRMS m/z calcd for C21H23NO2
321.1729; found 321.1728. Anal. Calcd for C21H23NO2: C 78.47, H
7.21, N 4.36. Found: C 78.61, H 7.14, N 4.25.
(1S,2S,3S)-2-[(4S)-4-Isopropyl-2-oxazolin-2-yl]-1-methoxy-3-methyl-
1-phenylcyclopropane (trans-12a): obtained as a mixture of diaste-
reoisomers (trans-12a/cis-12a, 83:17 and trans-12a/trans-13a, 92:8);
trans,trans-1-Butyl-2-(4,4-dimethyl-2-oxazolin-2-yl)-1-methoxy-
3-phenylclopropane (trans-4d): obtained as a single diastereoisomer;
1
1
oil; yield ) 90%; H NMR: δ ) 7.5-7.1 (m, 5 H), 4.0 (d, J ) 8.1
oil; yield ) 89%; H NMR: δ ) 7.5-7.2 (m, 5 H), 3.9 (dd, J ) 9.4,
Hz, 1H), 3.9 (d, J ) 8.1 Hz, 1H), 3.3 (s, 3H), 3.1 (d, J ) 7.2 Hz, 1H),
2.1 (d, J ) 7.2 Hz, 1H), 1.4 (s, 3H), 1.3 (s, 3H), 1.5-1.1 (m, 6H), 0.7
(t, J ) 6.5 Hz, 3H); 13C NMR: δ ) 162.7 (s), 135.9 (s), 128.6 (d, 4C),
126.2(d), 79.0 (t), 71.2 (s), 66.7 (s), 54.4 (q), 35.0 (d), 28.5 (t), 28.3
(q), 28.1 (q), 26.7 (t), 26.6 (d), 22.2 (t), 13.6 (q); HRMS m/z calcd for
C19H27NO2 301.2042; found 301.2039. Anal. Calcd for C19H27NO2: C
75.71, H 9.03, N 4.65. Found: C 75.49, H 9.14, N 4.55.
trans-2-(4,4-Dimethyl-2-oxazolin-2-yl)-1-methoxy-1-phenylcyclo-
propane (trans-4e): obtained as a mixture of diastereoisomers (trans-
4e/cis-4e, 68:32); oil; yield ) 84%; 1H NMR: δ ) 7.5-7.2 (m, 5 H),
3.6 (d, J ) 8.4 Hz, 1H), 3.5 (d, J ) 8.4 Hz, 1H), 3.1 (s, 3H), 2.2 (dd,
J ) 10.0, 7.0 Hz, 1H), 1.7 (dd, J ) 7.0, 6.3 Hz, 1H), 1.5 (dd, J )
7.9 Hz, 1H), 3.6 (m, 1H), 3.3 (dd, J ) 8.5, 7.9 Hz, 1H), 3.1 (s, 3H),
2.1 (m, 1H), 1.9 (d, J ) 6.8 Hz, 1H), 1.6 (m, 1H), 1.4 (d, J ) 6.1 Hz,
3H), 0.8 (d, J ) 6.8 Hz, 3H), 0.7 (d, J ) 6.8 Hz, 3H); 13C NMR: δ )
164.4 (s), 136.1 (s), 129.5 (d, 2C), 127.7 (d, 3C), 77.5 (s), 71.6 (d),
69.1 (t), 54.8 (q), 31.9 (d), 29.8 (d), 23.8 (d), 18.8 (q), 17.7 (q), 11.4
(q); HRMS m/z calcd for C17H23NO2 273.1729; found 273.1724. Anal.
Calcd for C17H23NO2: C 74.69, H 8.48, N 5.12. Found: C 74.73, H
8.44, N 5.23.
(1S,2S,3S)-2-[(4S)-4-Isopropyl-2-oxazolin-2-yl]-1-methoxy-1,3-
diphenylcyclopropane (trans-12b): obtained as a mixture of diaste-
reoisomers (trans-12b/cis-12b, 84:16); yield ) 94%; obtained as a
single product after recrystallization from pentane; white solid; mp

10500 J. Am. Chem. Soc., Vol. 123, No. 43, 2001
Barluenga et al.
86-88 °C; [R]20D ) -59.4 (c ) 0.55 in CHCl3); 1H NMR: δ ) 7.5-
7.2 (m, 10 H), 4.0 (dd, J ) 8.5, 7.9 Hz, 1H), 3.7 (m, 1H), 3.4 (dd, J
) 8.5, 8.2 Hz, 1H), 3.3 (d, J ) 7.3 Hz, 1H), 2.9 (s, 3H), 2.8 (d, J )
7.3 Hz, 1H), 1.6 (m, 1H), 0.9 (d, J ) 6.9 Hz, 3H), 0.8 (d, J ) 6.9 Hz,
3H); 13C NMR: δ ) 165.6 (s), 137.8 (s), 137.2 (s), 131.6 (d, 2C),
130.1 (d, 2C), 129.9 (d, 3C), 128.4 (d, 3C), 74.8 (s), 73.9 (d), 71.5 (t),
56.6 (q), 35.8 (d), 34.1 (d), 31.5 (d), 20.8 (q), 19.9 (q); HRMS m/z
calcd for C22H25NO2 335.1885; found 335.1880. Anal. Calcd for C22H25-
NO2: C 78.77, H 7.51, N 4.18. Found: C 78.61, H 7.39, N 4.21.
(1S,2S,3S)-1-Butyl-2-[(4S)-4-isopropyl-2-oxazolin-2-yl]-1-methoxy-
3-phenylcyclopropane (trans-12c): obtained as a mixture of diaste-
reoisomers (trans-12c/cis-12c, 58:42 and trans-12c/trans-13c, 85:15);
140.0 (s), 128.0 (d, 2C), 127.4 (d), 127.3 (d, 2C), 87.6 (d), 78.6 (t),
66.6 (s), 56.7 (q), 37.3 (d), 31.5 (t), 28.3 (q), 28.2 (q), 15.8 (q); HRMS
m/z calcd for C15H20NO2 [M - CH3]+ 246.1494; found 246.1496. Anal.
Calcd for C16H23NO2: C 73.53, H 8.87, N 5.36. Found: C 73.76, H
8.72, N 5.30.
(1S,2S)/(1R,2R)-3-(4,4-Dimethyl-2-oxazolin-2-yl)-1-isopropoxy-2-
methyl-1-phenylpropane (5g): obtained as a single diastereoisomer;
1
oil; yield ) 90%; H NMR: δ ) 7.3-7.2 (m, 5 H), 4.1 (d, J ) 6.9
Hz, 1H), 3.8 (s, 2H), 3.4 (m, 1H), 2.7 (dd, J ) 10.8, 2.8 Hz, 1H),
2.1(m, 2H), 1.2 (s, 6H), 1.1 (d, J ) 6.2 Hz, 3H), 1.0 (d, J ) 6.2 Hz,
3H), 0.8 (d, J ) 6.4 Hz, 3H); 13C NMR: δ ) 165.3 (s), 141.6 (s),
127.7 (d, 2C), 127.2 (d, 2C), 127.0 (d), 87.6 (d), 78.5 (t), 68.6 (d),
66.6 (s), 37.5 (d), 31.1 (t), 28.3 (q), 28.2 (q), 23.2 (q), 20.8 (q), 15.8
(q); HRMS m/z calcd for C15H20NO2 [M-C3H7]+ 246.1494; found
246.1491. Anal. Calcd for C18H27NO2: C 74.70, H 9.40, N 4.84.
Found: C 74.88, H 9.36, N 4.91.
1
oil; yield ) 90%; H NMR: δ ) 7.3-7.0 (m, 5H), 4.2 (m, 1H), 3.9
(m, 2H), 3.3 (s, 3H), 3.1 (d, J ) 7.0 Hz, 1H), 2.1 (d, J ) 7.0 Hz, 1H),
1.7 (m, 1H), 1.4-1.0 (m, 6H), 0.9 (d, J ) 6.8 Hz, 3H); 0.8 (d, J ) 6.8
Hz, 3H), 0.7 (t, J ) 7.1 Hz, 3H); 13C NMR: δ ) 164.0 (s), 135.9 (s),
128.0 (d, 4C), 126.1 (d), 71.7 (d), 71.0 (s), 69.9 (t), 54.3 (q), 34.6 (d),
32.3 (d), 28.5 (t), 26.8 (d), 26.7 (t), 22.1 (t), 18.5 (q), 17.7 (q), 13.6
(q); HRMS m/z calcd for C20H29NO2 315.2198; found 315.2194. Anal.
Calcd for C20H29NO2: C 76.15, H 9.27, N 4.44. Found: C 76.34, H
9.35, N 4.31.
(2S)/(2R)-3-(4,4-Dimethyl-2-oxazolin-2-yl)-2-methoxy-1,2-diphen-
ylpropane (6): obtained as a single diastereoisomer; oil; yield ) 95%;
1H NMR: δ ) 7.4-7.1 (m, 8 H), 6.9 (m, 2H), 4.0 (s, 2H), 3.5 (d, J )
13.2 Hz, 1H), 3.3 (s, 3H), 3.2 (d, J ) 13.2 Hz, 1H), 2.9 (s, 2H), 1.3 (s,
3H), 1.2 (s, 3H); 13C NMR: δ ) 162.7 (s), 142.0 (s), 136.7 (s), 130.8
(d, 2C), 127.8 (d, 2C), 127.4 (d, 2C), 127.1 (d), 126.8 (d, 2C), 126.1
(d), 81.1 (t), 79.0 (s), 66.5 (s), 50.9 (q), 44.7 (t), 33.2 (t), 28.1 (q, 2C);
HRMS m/z calcd for C20H22NO2 [M - CH3]+ 308.1650; found
308.1646. Anal. Calcd for C21H25NO2: C 77.98, H 7.79, N 4.33.
Found: C 77.79, H 7.71, N 4.31.
(1S,2S)-3-[(4S)-4-Isopropyl-2-oxazolin-2-yl]-1-methoxy-2-methyl-
1-phenylpropane (14a): obtained as a mixture of diastereoisomers
(14a/15a, 77:23); oil; yield ) 92%; 1H NMR: δ ) 7.4-7.2 (m, 5 H),
4.2 (m, 1H), 3.9 (m, 3H), 3.1 (s, 3H), 2.7 (m, 1H), 2.2 (m, 2H), 1.7
(m, 1H), 1.0 (d, J ) 6.4 Hz, 3H), 0.9 (d, J ) 6.8 Hz, 3H), 0.7 (d, J )
6.4 Hz, 3H); 13C NMR: δ ) 166.5 (s), 140.1 (s), 128.0 (d, 2C), 127.4
(d, 3C), 87.6 (d), 71.8 (d), 69.5 (t), 56.7 (q), 37.3 (d), 32.5 (d), 31.4
(t), 18.7 (q), 18.0 (q), 15.9 (q); HRMS m/z calcd for C16H22NO2 [M -
CH3]+ 260.1650; found 260.1648. Anal. Calcd for C17H25NO2: C 74.14,
H 9.15, N 5.09. Found: C 74.35, H 9.11, N 5.13.
(1S,2S)-1-Isopropoxy-3-[(4S)-4-isopropyl-2-oxazolin-2-yl]-2-meth-
yl-1-phenylpropane (14d): obtained as a mixture of diastereoisomers
(14d/15d, 88:12); oil; yield ) 94%; 1H NMR: δ ) 7.4-7.1 (m, 5 H),
4.1 (m, 1H), 4.0 (d, J ) 7.0 Hz, 1H), 3.9 (m, 2H), 3.4 (m, 1H), 2.7 (d,
J ) 11.7 Hz, 1H), 2.1 (m, 2H), 1.7 (m, 1H), 1.1 (d, J ) 7.0 Hz, 3H),
1.0 (d, J ) 6.2 Hz, 3H), 0.9 (d, J ) 6.2 Hz, 3H), 0.8 (d, J ) 6.2 Hz,
3H), 0.7 (d, J ) 6.5 Hz, 3H); 13C NMR: δ ) 166.8 (s), 141.7 (s),
127.8 (d, 2C) 127.0 (d, 3C), 82.6 (d), 71.8 (d), 69.5 (t), 68.7 (d), 37.6
(d), 32.5 (d), 31.1 (t), 20.9 (q), 18.7 (q), 18.0 (q), 16.0 (q), 14.4 (q);
HRMS m/z calcd for C19H29NO2 303.2198; found 303.2195. Anal. Calcd
for C19H29NO2: C 75.21, H 9.63, N 4.62. Found: C 74.19, H 9.49, N
4.69.
(1S,2S,3S)-1-Isopropoxy-2-[(4S)-4-isopropyl-2-oxazolin-2-yl]-3-
methyl-1-phenylcyclopropane (trans-12d): obtained as a mixture of
diastereoisomers (trans-12d/cis-12d, 90:10 and trans-12d/trans-13d,
1
95:5); oil; yield ) 86%; H NMR: δ ) 7.5-7.1 (m, 5 H), 3.9 (dd, J
) 9.5, 8.2 Hz, 1H), 3.7 (m, 2H), 3.4 (dd, J ) 9.5, 9.0 Hz, 1H), 2.0 (m,
1H), 1.8 (d, J ) 7.0 Hz, 1H), 1.6 (m, 1H), 1.3 (d, J ) 6.1 Hz, 3H), 1.0
(d, J ) 6.1 Hz, 3H), 0.95 (d, J ) 6.1 Hz, 3H), 0.9 (d, J ) 6.7 Hz, 3H),
0.8 (d, J ) 6.7 Hz, 3H); 13C NMR: δ ) 164.8 (s), 138.1 (s), 129.6 (d,
2C), 127.6 (d, 3C), 71.7 (d), 70.4 (s), 69.5 (d), 69.2 (t), 32.6 (d), 29.7
(d), 24.1 (d), 23.0 (q), 22.8 (q), 18.7 (q), 17.9 (q), 12.2 (q); HRMS m/z
calcd for C16H20NO2 [M-C3H7]+ 258.1494; found 258.1492. Anal.
Calcd for C19H27NO2: C 75.71, H 9.03, N 4.65. Found: C 75.58, H
9.09, N 4.72.
(1S,2S,3S)-2-[(4S)-4-tertButyl-2-oxazolin-2-yl]-1-methoxy-3-meth-
yl-1-phenylcyclopropane (trans-12e): obtained as a mixture of dia-
stereoisomers (trans-12e/cis-12e, 85:15), yield ) 87%; obtained as a
single diastereoisomer after recrystallization from pentane; white solid;
1
mp 82-84 °C; [R]20 ) - 61.7 (c ) 0.53 in CHCl3); H NMR: δ )
D
7.5-7.2 (m, 5 H), 3.9 (dd, J ) 9.7, 8.0 Hz, 1H), 3.7 (dd, J ) 9.7, 9.0
Hz, 1H), 3.3 (dd, J ) 9.0, 8.0 Hz, 1H), 3.2 (s, 3H), 2.1 (m, 1H), 1.9
(d, J ) 7.0 Hz, 1H), 1.4 (d, J ) 6.1 Hz, 3H), 0.8 (s, 9H); 13C NMR:
δ ) 164.2 (s), 136.1 (s), 129.4 (d, 2C), 127.6 (d, 3C), 75.4 (d), 71.7
(s), 67.7 (t), 54.7 (q), 32.9 (s), 30.0 (d), 25.8 (q, 3C), 23.8 (d), 11.4
(q); HRMS m/z calcd for C18H25NO2 287.1885; found 287.1882. Anal.
Calcd for C18H25NO2: C 75.22, H 8.77, N 4.87. Found: C 75.09, H
8.86, N 4.75.
(1S,2S,3S)-2-[(4S)-4-tertButyl-2-oxazolin-2-yl]-1-isopropoxy-3-
methyl-1-phenylcyclopropane (trans-12f): obtained as a mixture of
diastereoisomers (trans-12f/cis-12f, 94:6); oil; yield ) 86%; 1H
NMR: δ ) 7.4-7.1 (m, 5 H), 3.8 (dd, J ) 9.5, 8.1 Hz, 1H), 3.6 (m,
2H), 3.3 (dd, J ) 9.0, 8.1 Hz, 1H), 2.0 (m, 1H), 1.3 (d, J ) 6.1 Hz,
(1S,2S)-3-[(4S)-4-tertButyl-2-oxazolin-2-yl]-1-methoxy-2-methyl-
1-phenylpropane (14e): obtained as a mixture of diastereoisomers (14e/
15e, 78:22); yield ) 93%; obtained as well from pure 12e as a mixture
of diastereoisomers (14e/15e, 93:7); obtained as a single diastereoisomer
3H), 1.0 (d, J ) 7.9 Hz, 3H), 0.9 (d, J ) 7.9 Hz, 3H), 0.8 (s, 9H); 13
C
after recrystallization from pentane; white solid; mp 72-74 °C; [R]20
D
) - 102.0 (c ) 1.02 in CHCl3); 1H NMR: δ ) 7.4-7.2 (m, 5 H), 4.1
(m, 2H), 3.8 (m, 2H), 3.2 (s, 3H), 2.7 (dd, J ) 13.6, 2.3 Hz, 1H), 2.2
(m, 2H), 0.9 (s, 9H), 0.8 (d, J ) 6.4 Hz, 3H); 13C NMR: δ ) 166.5
(s), 140.6 (s), 128.0 (d, 2C), 127.4 (d, 3C), 87.5 (d), 75.6 (d), 68.1 (t),
56.7 (q), 37.4 (d), 33.5 (s), 31.3 (t), 25.7 (q, 3C), 15.8 (q); HRMS m/z
calcd for C18H27NO2 289.2042; found 289.2037. Anal. Calcd for C18H27-
NO2: C 74.70, H 9.40, N 4.84. Found: C 74.86, H 9.36, N 4.78.
(1S,2S)-3-[(4S)-4-tertButyl-2-oxazolin-2-yl]-1-isopropoxy-2-meth-
yl-1-phenylpropane (14f): obtained as a mixture of diastereoisomers
NMR: δ ) 164.8 (s), 138.1 (s), 129.7 (d, 2C), 127.7 (d), 127.6 (d,
2C), 75.5 (d), 70.5 (s), 69.5 (d), 67.8 (t), 33.1 (s), 30.0 (d), 25.9 (q,
3C), 24.2 (d), 23.0 (q), 22.8 (q), 12.3 (q); HRMS m/z calcd for C20H29-
NO2 315.2198; found 315.2201. Anal. Calcd for C20H29NO2: C 76.15,
H 9.27, N 4.44. Found: C 75.97, H 9.49, N 4.31.
Hydrogenolysis of Cyclopropanes 4, 12, and 13. General Pro-
cedure. A suspension of Pd/C (10%, 106 mg, 0.1 mmol) in 20 mL of
THF was saturated with hydrogen. Then, triethylamine (0.1 mL, 0.7
mmol) and the corresponding cyclopropane 4a,c,g (1 mmol) were
added, and the mixture was treated with hydrogen at atmospheric
presure. After vigorous stirring for 12 h, the mixture was filtered over
Celite, the solvent was removed, and the crude product was purified
by column chromatography (silica gel, hexanes/AcOEt, 1:1).
1
(14f/15f, 91:9); oil; yield ) 91%; H NMR: δ ) 7.4-7.2 (m, 5 H),
4.1 (m, 3H), 3.9 (m, 1H), 3.4 (m, 1H), 2.7 (m, 1H), 2.1 (m, 2H), 1.2
(d, J ) 6.2 Hz, 3H), 1.1 (d, J ) 6.2 Hz, 3H), 0.9 (s, 9H), 0.8 (d, J )
6.2 Hz, 3H); 13C NMR: δ ) 166.7 (s), 141.5 (s), 127.8 (d, 2C), 127.2
(d, 2C), 127.1 (d), 82.5 (d), 75.4 (d), 68.6 (d), 68.0 (t), 37.6 (d), 33.4
(s), 30.9 (t), 25.6 (q, 3C), 23.2 (q), 20.9 (q), 15.8 (q); HRMS m/z calcd
for C17H24NO2 [M-C3H7]+ 274.1807; found 274.1804. Anal. Calcd
for C20H31NO2: C 75.67, H 9.84, N 4.41. Found: C 75.59, H 9.90, N
4.49.
(1S,2S)/(1R,2R)-3-(4,4-Dimethyl-2-oxazolin-2-yl)-1-methoxy-2-
methyl-1-phenylpropane (5a): obtained as a single diastereoisomer;
oil; yield ) 93%; 1H NMR: δ ) 7.4-7.2 (m, 5 H), 3.8 (s, 2H), 3.7 (d,
J ) 7.4 Hz, 1H), 3.1 (s, 3H), 2.6 (dd, J ) 13.6, 3.8 Hz, 1H), 2.2 (m,
2H), 1.2 (s, 6H), 0.7 (d, J ) 6.7 Hz, 3H); 13C NMR: δ ) 165.4 (s),

Oxazolines for EnantioselectiVe Cyclopropanation
J. Am. Chem. Soc., Vol. 123, No. 43, 2001 10501
Table 4. Crystal Data and Structure Refinement for 14e
(2S)-1-[(4S)-4-Isopropyl-2-oxazolin-2-yl]-2-methoxy-2,3-diphenyl-
propane (16): obtained as a single diastereoisomer, oil; yield ) 96%;
[R]20D ) - 59.7 (c ) 0.64 in CHCl3); 1H NMR: δ ) 7.4-6.9 (m, 10
H), 4.3 (m, 1H), 4.0 (m, 2H), 3.5 (d, J ) 13.1 Hz, 1H), 3.3 (s, 3H), 3.2
(d, J ) 13.1 Hz, 1H), 3.0 (s, 2H), 1.8 (m, 1H), 1.0 (d, J ) 6.5 Hz,
3H), 0.9 (d, J ) 6.5 Hz, 3H); 13C NMR: δ ) 163.9 (s), 141.9 (s),
136.7 (s), 130.8 (d, 2C), 127.8 (d, 2C), 127.3 (d, 2C), 127.1 (d), 126.7
(d, 2C), 126.0 (d), 80.1 (s), 71.8 (d), 69.7 (t), 50.8 (q), 44.8 (t), 32.6
(t), 32.5 (d), 18.7 (q), 18.0 (q); HRMS m/z calcd for C22H27NO2
337.2042; found 337.2034. Anal. Calcd for C22H27NO2: C 78.30, H
8.06, N 4.15. Found: C 78.39, H 7.98, N 4.21.
Elaboration of the Oxazoline Moiety. Synthesis of Alcohols 9
and 11. To a solution of compounds 5, 6, 14, or 16 (1 mmol) in
CH2Cl2 (10 mL), 5% aqueous Na2CO3 (10 mL) and CBzCl (1.5 mmol)
was added. The mixture was stirred overnight and, after addition of
water (50 mL), extracted with CH2Cl2. The combined organic phases
were washed first with 5% aqueous Na2CO3, second with water, and
then dried. The solvent was removed and the residue dissolved in
toluene (20 mL) and treated with DIBAL-H (1 M toluene, 1.5 mL, 1.5
mmol) at -78 °C (compounds 5 and 14) or in THF and treated with
LiAlH4 (1.5 mmol) (compounds 6 and 16) at 0 °C. The mixture was
allowed to warm and, after stirring for 2 h at room temperature,
quenched with H2O and extracted with Et2O. The combined organic
phases were washed with H2O and dried. The solvent was removed
and the crude purified by column chromatography (silica gel, hexanes/
EtOAc 3:1).
(3S,4S)-4-Methoxy-3-methyl-4-phenylbutan-1-ol (9a): obtained as
a single diastereoisomer from crystallized oxazoline 14e; oil; yield )
71%; [R]20D ) - 113.8 (c ) 0.65 in CHCl3); 1H NMR: δ ) 7.4-7.2
(m, 5 H), 3.9 (d, J ) 7.9 Hz, 1H), 3.7 (m, 2H), 3.2 (s, 3H), 2.3 (brs,
1H), 1.9 (m, 2H), 1.6 (m, 1H), 0.7 (d, J ) 6.7 Hz, 3H); 13C NMR: δ
) 142.5 (s), 130.1 (d, 2C), 129.5 (d), 129.4 (d, 2C), 91.0 (d), 60.1 (t),
58.7 (q), 39.3 (d), 38.7 (t), 19.2 (q); HRMS m/z calcd for C12H18O2
194.1307; found 194.1316. Anal. Calcd for C12H18O2: C 74.19, H 9.34.
Found: C 74.31, H 9.23. HPLC (phenylcarbamate derivative): Chiracel
OD-H, hexane/2-propanol, 3:1, flow rate 0.8 mL/min, tR ) 36.8 (3S,4S),
tR ) 48.7 (3R,4R).
identification code
empirical formula
formula weight
14e
C18H27NO2
289.41
200(2) K
temperature
wavelength
crystal system, space group
unit cell dimensions
0.71073 A
monoclinic, P21
a ) 7.407(4) Å
b ) 12.392(3) Å â ) 102.58(2)°
c ) 9.432(6) Å
844.9(7) Å3
volume
Z, calculated density
absorption coefficient
F(000)
2, 1.138 Mg/m3
0.073 mm-1
316
crystal size
θ range for data collection
index ranges
0.30 mm × 0.16 mm × 0.13 mm
2.21-25.97°
0 e h e 9, 0 e k e 15, -11 e l e 11
reflections collected/unique 1871/1736 [R(int) ) 0.0321]
completeness to 2θ ) 25.97 100.0%
absorption correction
refinement method
data/restraints/parameters
goodness-of-fit on F2
final R indices [I > 2σ(I)]
R indices (all data)
none
full-matrix least-squares on F2
1736/1/261
1.033
R1 ) 0.0380, wR2 ) 0.0820
R1 ) 0.1009, wR2 ) 0.1015
0.195 and -0.212 e‚Å-3
largest diff. peak and hole
corrections were applied. The structure was solved by direct methods
using SHELXS97.26 Isotropic least-squares refinement on F2 using
SHELXL97.27 During the final stages of the refinements, all positional
parameters and the anisotropic temperature factors of all the non-H
atoms were refined. The H-atoms were located by Fourier defference
synthesis and refined free or riding with common isotropic thermal
parameters. The function minimized was ([ΣwFo - Fc2)/Σw(Fo )]1/2
2
2
where w ) 1/[σ2(Fo ) + (0.0510P)2] with σ(Fo ) from counting sta-
2
2
2
tistics and P ) (Max(Fo , o) + 2* Fc2)/3. Atomic scattering factors
were taken from International Tables for X-ray Crystallography.28 Plots
were made with the EUCLID package.29 Geometrical calculations were
made with PARST.30 All calculations were made at the Scientific
Computer Centre of the University of Oviedo and on the X-ray group
computers.
(3S,4S)-4-Isopropoxy-3-methyl-4-phenylbutan-1-ol (9b): obtained
from 14f/15f as a mixture of diastereoisomers (9b/10b, 91:9), oil; yield
) 75%; 1H NMR: δ ) 7.4-7.2 (m, 5 H), 4.1 (d, J ) 7.4 Hz, 1H), 3.7
(m, 2H), 3.5 (m, 1H), 3.2 (brs, 1H), 1.9 (m, 2H), 1.6 (m, 1H), 1.2 (d,
The most relevant crystal and refinement data are collected in Table
4. The unit-cell dimensions were determined from the angular settings
of 25 reflections in the range 10 e θ e 15°. The space group was
inferred to be P21 from systematic absences and structure determination.
Absolute configuration was assumed based on the knowledge of
configuration of C(3).
J ) 6.1 Hz, 3H), 1.1 (d, J ) 6.1 Hz, 3H), 0.7 (d, J ) 7.9 Hz, 3H); 13
C
NMR: δ ) 141.9 (s), 128.0 (d, 2C), 127.3 (d, 3C), 83.9 (d), 68.9 (d),
61.1 (t), 38.1 (d), 36.5 (t), 23.2 (q), 20.6 (q), 17.7 (q); HRMS m/z calcd
for C14H22O2 222.1620; found 222.1620. Anal. Calcd for C14H22O2: C
75.63, H 9.97. Found: C 75.69, H 10.06. HPLC (phenylcarbamate
derivative): Chiracel OD-H, hexane/2-propanol, 3:1, flow rate 0.8 mL/
min, tR ) 24.7 (3S,4S), tR ) 48.4 (3R,4R).
Acknowledgment. Financial support from Ministerio de
Educacio´n y Ciencia (DGICYT, PB97-1271 and CICYT,
BQU2000-0219) is gratefully acknowledged.
(3S)-3-Methoxy-3-phenyl-4-phenylbutan-1-ol (11): Oil; yield )
1
74% from 16; [R]20 ) -32.9 (c ) 0.45 in CHCl3); H NMR: δ )
D
7.4-7.1 (m, 8 H), 6.8 (m, 2H), 3.8 (t, J ) 5.1 Hz. 2H), 3.3 (s, 3H), 3.2
(s, 2H), 2.5 (brs, 1H), 2.2 (m, 2H); 13C NMR: δ ) 142.6 (s), 136.4 (s),
130.2 (d, 2C), 127.9 (d, 2C), 127.6 (d, 2C), 127.0 (d), 126.5 (d, 2C),
126.1 (d), 81.8 (s), 58.7 (t), 50.2 (q), 44.3 (t), 36.0 (t); HRMS m/z
calcd for C15H15O [M-C2H50]+ 211.1123; found 211.1121. Anal. Calcd
for C17H20O2: C 79.65, H 7.86. Found: C 79.73, H 7.83. HPLC:
Supporting Information Available: Details and tables for
X-ray crystal structures of 14e (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
JA010719M
(25) (a) Lehman, M. S.; Larsem, F. K. Acta Crystallogr. A 1974, 30,
580. (b) Grant, D. F.; Gabe, E.F. J. Appl. Crystallogr. 1978, 11, 114.
(26) Sheldrick, G. M. SHELXS-97, Program for the Solution of Crystal
Structures; University of Go¨ttingen, Germany, 1997.
(27) Sheldrick, G. M., SHELXS-97, Program for the Refinement of
Crystal Structures; University of Go¨ttingen, Germany, 1997.
(28) International Tables for X-ray Crystallography; Birmingham: Kynoch
Press, 1974; Vol. IV (Present distributor: Kluwer Academic Publishers:
Dordrecht).
Chiracel OD-H, hexane/ethanol, 150:1, flow rate 0.85 mL/min, tR
57.8 (S), tR ) 63.2 (R).
)
X-ray Crystal Structure Determination. Data for 14e were
collected on a Nonius CAD4 single-crystal diffractometer. The intensi-
ties were measured using the ω-2θ scan technique with a scan angle
of 1.5° and a variable scan rate with a maximum scan time of 60 s per
reflection. The intensity of the primary beam was checked throughout
the collection by monitoring three standard reflections every 60 min.
On all reflections, profile analysis was performed.25 Symmetry-
equivalent reflections were averaged, and Lorentz and polarization
(29) Spex, A. L. In Computational Crystallography; Sayre, D., Ed.;
Clarendon Press: Oxford, 1983; p 95.
(30) Nardelli, A. Comput. Chem. 1983, 7, 95.