Ring-conformer effects of the cyclopropyl group: First use of trans-(2r,3r)-cyclopropanecarbaldehydes as electrophiles in diastereoselective baylisihillman reaction

Article abstract of DOI:10.1055/s-0029-1218019

trans-(2R,3R)-Cyclopropanecarbaldehydes are used as novel electrophiles in the Baylis-Hillman reaction to afford adducts in good yields (75-85%) and diastereoselectivities (60-90%).

Full text of DOI:10.1055/s-0029-1218019

LETTER
2605
Ring-Conformer Effects of the Cyclopropyl Group: First Use of trans-(2R,3R)-
Cyclopropanecarbaldehydes as Electrophiles in Diastereoselective Baylis–
Hillman Reaction
R
ing-Conform
a
er
E
ffects
o
l
f
Cycl
a
o
k
up in
S
tereo
o
c
ontrol dety Radha Krishna,* S. Kishore, P. Srinivas Reddy
D-211, Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology, Hyderabad 500 607, India
Fax +91(40)27160387; E-mail: prkgenius@iict.res.in
Received 22 July 2009
EWG
X
X
H
*
Abstract: trans-(2R,3R)-Cyclopropanecarbaldehydes are used as
novel electrophiles in the Baylis–Hillman reaction to afford adducts
in good yields (75–85%) and diastereoselectivities (60–90%).
X = O
H
R
H
R
H
CHO
+
EWG
ref. 5
route A
OH
ref. 6
route B
Key words: trans-(2R,3R)-cyclopropanecarbaldehydes, Baylis–
Hillman reaction, electrophiles, diastereoselectivity
X
H
R = H
X = NTs
H
R
EWG
*
Highly strained cyclopropane ring present in a wide vari-
ety of naturally occurring compounds1 had prompted the
development of the chemistry of cyclopropanes. Addi-
tionally, many quinolone antibiotics2 such as ciprofloxa-
cin, agrochemicals like chrysanthemic acid3 and
anticancer compounds4 contain a cylcopropane ring, and
OH
EWG
H
R
H
route C
R
H
H
CHO
+
EWG
*
OH
the activity of these products is often attributed to it. Inter- Scheme 1 Different three-membered ring carboxaldehydes in
Baylis–Hillman reaction
estingly, either incorporation or deletion of cyclopropane
rings in a bioactive chemical entity increases or decreases
the activity of the molecule under consideration mostly
the restricted ring system that tend to dictate the overall
due to the unsaturated character that it adds up or other-
outcome.
wise. Earlier,5 we reported the first use of cis-2,3-epoxy
To the best of our knowledge, so far, chiral cyclopropan-
ecarboxaldehydes and more so the trans-(2R,3R)-cyclo-
aldehydes in diastereoselective Baylis–Hillman reaction
(Scheme 1, route A) to result in adducts with considerable
propanecarbaldehydes
were
never
utilized
as
selectivities, while the aziridines-2-(S)-carboxaldehydes6
reportedly gave the corresponding adducts in low diaste-
reoselectivity (Scheme 1, route B). It is well documented
in the literature7 that heteroatom-containing three-mem-
bered rings like epoxides, aziridines, and episulfides at-
tain different ring conformations than their cyclopropane
congeners and quite understandably possess different
properties owing to the presence of heteroatom. Analo-
gously, cyclopropanecarbaldehydes assume differential
spatial arrangement in their transition states,8 and their
importance in synthetic organic chemistry as valuable
starting materials gave us impetus to consider them in
Baylis–Hillman reaction. In addition to the above-cited
unique properties of cyclopropanecarbaldehydes and our
own interest in asymmetric Baylis–Hillman reaction,9
herein substituted trans-(2R,3R)-cyclopropanecarbalde-
hydes are explored as novel electrophiles for the first time
in Baylis–Hillman reaction. The reason for their choice is
twofold: firstly, to check if there are any diastereodiffer-
entiating effects and, secondly, any steric effects due to
electrophiles in Baylis–Hillman reaction. The results em-
anating from the study are presented herein (Scheme 1,
route C).
Though several methods have been reported for accessing
trans-(2R,3R)-cyclopropanecarbaldehydes,10 we chose
the practical method of their preparation from epoxides
via the Horner–Wadsworth–Emmons (HWE)-type reac-
tion.11
The strategy stems from the fact that chiral terminal ep-
oxides could be accessed through the Jacobsen’s HKR
which in turn could be converted into chiral cyclopropyl
esters and thence into aldehydes in optically pure form
with predictable stereochemistry. Thus, while the config-
uration is inverted at C2 carbon of epoxide, the newly cre-
ated carbonyl-bearing carbon assumes a relative trans-
geometry. A converse trans-cyclopropyl ester is obtained
from the enantiomeric epoxide starting material. Thus, 1-
alkene i on epoxidation–Jacobsen’s hydrolytic kinetic res-
olution,12 HWE reaction gave the chiral cyclopropyl ester
iv. Later, the thus generated cyclopropyl ester on further
transformations gave the corresponding aldehyde v
(Scheme 2). The absolute stereochemistry of the cyclo-
propyl esters and the aldehydes thereof were deduced
based on the literature evidence.11
SYNLETT 2009, No. 16, pp 2605–2608
x
x
.x
x
.2
0
0
9
Advanced online publication: 10.09.2009
DOI: 10.1055/s-0029-1218019; Art ID: G18109ST
© Georg Thieme Verlag Stuttgart · New York

2606
P. Radha Krishna
LETTER
O
Table 1 Baylis–Hillman Reaction of trans-(2R,3R)-Cyclopropane-
MCPBA, CHCl3
(S,S)-(salen)CoIII(OAc)
Jacobsen's HKR
carbaldehydes with Olefinsa
R
R
0 °C
i
ii
Productb Yield de anti/
(%)c syn (%)d
O
Entry Aldehyde
TEPA, KOt-Bu
DME, 60 °C
R
H
R
COOEt
H
iii
iv
4a
5a
82
88
95:5
95:5
1
H
CHO
R
1. LAH, THF, 0 °C
BnO
H
7
H
H
2. (COCl)2, DMSO
Et3N, CH2Cl2, –78 °C
CHO
H
4b
5b
80
85
85:15
87:13
v
BnO
2
H
CHO
H
Scheme 2 General synthetic scheme for the preparation of cyclo-
propyl aldehydes
4c
5c
80
82
90:10
90:10
3
H
CHO
BnO
After having identified a synthetic protocol for accessing
cyclopropanecarbaldehydes, a test Baylis–Hillman reac-
tion of trans-(2R,3R)-cyclopropanecarbaldehyde 1a with
ethyl acrylate (2) or acrylonitrile (3) was tried under sev-
eral solvents like THF, 1,4-dioxane–H2O, DMF, and
DMSO catalyzed by DABCO. Out of all the trials, the
reaction in DMSO resulted in adducts 4a and 5a, respec-
tively, in high diastereoselectivity and good yields
(Scheme 3, Table 1).
4d
5d
82
85
92:8
92:8
4
H
CHO
BnO
H
4e
5e
80
85
80:20
80:20
5
H
BnO
CHO
H
F
4f
5f
85
85
85:15
87:13
6
H
CHO
O
H
O
4g
5g
75
80
85:15
85:15
O
7
8
O
EWG
DABCO
R
R
H
H
H
CHO
+
H
EWG
DMSO, r.t., 12–15 h
H
MeO
H
CHO
OH
1a–h
2 EWG = COOEt
3 EWG = CN
4a–h
5a–h
O
4h
5h
80
85
80:20
80:20
Scheme 3
O
H
BnO
CHO
H
Inspired by the result, several aldehydes decorated with
varied functional groups, such as possessing 3-alkoxy
substituents or otherwise, were selected for the Baylis–
Hillman reaction in order to define the role of the substit-
uents for any possible secondary interactions or steric fac-
tors that might influence the stereochemical outcome.
Thus, firstly aldehydes 1a–d bearing 3-n-alkyl groups
with varied chain length were subjected to Baylis–Hill-
man reaction under the optimized conditions to afford 4a–
d and 5a–d as adducts in uniformly good yields and de
(entries 1–4, Table 1). Later, the other set of aldehydes
1e–h, those decorated with 3-alkoxy substitutions were
subjected to Baylis–Hillman reaction under similar reac-
tion conditions, with olefins 2 and 3, to afford the corre-
sponding adducts 4e–h and 5e–h (entries 5–8, Table 1) in
comparable yields albeit in lesser de.13,14 The factors re-
sponsible for such dramatic difference will be discussed
later.
a Aldehyde (1.0 mmol) in DMSO (1.0 mL) was added DABCO (0.5
mmol) and the olefin (1.5 mmol) and the mixture stirred at r.t. for 12–
15 h.
b All the products are characterized by their spectral data.
c Combined yield.
d As determined by 1H NMR.
ic protons at d = 6.23 ppm as a singlet for minor isomer
(0.15 H), d = 6.18 ppm for the major isomer (0.85 H), d =
5.82 ppm as a singlet for minor isomer (0.15 H), and d =
5.78 ppm as a singlet for major isomer (0.85 H) while the
anomeric proton resonated at d = 6.09 ppm as a doublet
(J = 2.9 Hz) for the minor isomer (0.15 H), d = 5.90 ppm
as a doublet (J = 3.9 Hz) for the major isomer (0.85 H).
The allylic proton resonated at d = 5.00 ppm as a triplet
(J = 6.2 Hz) for the minor isomer (0.15 H) and d = 4.8
ppm as a triplet (J = 6.6 Hz) for the major isomer (0.85 H).
The de were also evaluated by HPLC and found consistent
with NMR calculations.
The diastereomeric ratio in 4a was evaluated based on the
relative integration of the differential protons. For in-
stance, 1H NMR of 4a displays the diagnostic olefinic pro-
tons at d = 6.21 ppm as a singlet for the major isomer (0.95
H), at d = 6.15 ppm as a singlet for the minor isomer (0.05
H), at d = 5.83 ppm as a singlet for the major isomer (0.95
H), and at d = 5.80 ppm as a singlet for the minor isomer
(0.05 H). The allylic proton resonated at d = 4.37 ppm as
a doublet of doublet (J = 4.0, 8.0 Hz) integrating for one
proton. Similarly, the 1H NMR of 4g displayed the olefin-
The absolute stereochemistry of the newly created center
in 4a was initially determined based on the transition
models (Figure 1) as well as on the literature evidence.8 It
is well known that cyclopropanecarbaldehydes exist in bi-
sected conformations, namely s-cis and s-trans conform-
ers wherein cyclopropane ring exists predominantly in s-
trans form (Figure 1). Consequently, nucleophilic attack
occurs via these bisected conformations, that is, from the
less hindered si-face facilitated by the strong interactions
between the cyclopropane electrons (strong p-donor) and
Synlett 2009, No. 16, 2605–2608 © Thieme Stuttgart · New York

LETTER
Ring-Conformer Effects of Cyclopropyl Group in Stereocontrol
2607
the antibonding orbital of the incipient bond of the nucleo- sponding adducts in good yields and selectivities. It was
phile and the carbonyl carbon to result in the formation of found that the ring conformation and substituents play de-
major anti product. Thus, the major isomer was assigned cisive role in the stereoselection of the product largely in
as S-isomer (anti-isomer) and the minor as R. However, favor of anti isomer. While the 3-alkyl-substituted alde-
for the alkoxy-substituted aldehydes, weak interactions15 hydes 1a–d possessing nonparticipating group gave anti
between the enolate and alkoxy group(s) of the cyclopro- product in greater ratios, the 3-alkoxy-substituted trans-
panecarbaldehyde(s) stabilizes the s-cis transition state to (2R,3R)-cyclopropanecarbaldehydes 1e–h furnished ad-
result in syn products alongside.
ducts in comparatively lower selectivities due to de-
creased facial selectivity. An investigation into the utility
of the adduct in the total synthesis of solandelactone E17 is
in progress.
H
O
Nu
Nu
H
H
anti-product
syn-product
O
S-cis
R
H
R
Acknowledgment
S-trans
Authors (S.K.) and (P.S.R.) thank the CSIR, New Delhi, for finan-
cial support in the form of fellowships. We are thankful to the De-
partment of Science and Technology, New Delhi, for the financial
assistance of the Grants-in-Aid project under SERC (No. SR/S1/
OC-59/2006).
Figure 1 Transition-state models
Further, to assign the absolute stereochemistry unambigu-
ously, Mosher esters of 4a were prepared (Scheme 4) and
their NMR studied. For instance, in the 1H NMR spectrum
of 6, the ester attached proton (H3) appeared at d = 5.85
ppm as a doublet for the major isomer while the same pro-
ton appeared at d = 4.85 ppm in ester 7 (major isomer).
Since the H3 of (3S,2¢R)-ester 6 was found to be the most
deshielded, it can be deduced and unequivocally estab-
lished that the absolute stereochemistry of the newly cre-
ated carbon atom in adduct 4a to be ‘S’ for the major
isomer in accordance with the conformational models of
MPA-esters.16 Analogously, the absolute stereochemistry
of the newly created stereogenic center in all other ad-
ducts (major isomer) was assigned as ‘S’.
References and Notes
(1) Donaldson, W. A. Tetrahedron 2001, 57, 8589.
(2) Quinolones; Andriole, V. T., Ed.; Academic Press: London,
2000.
(3) (a) Recent Advances in the Chemistry of Insect Control;
James, N. F., Ed.; RCS: London, 1985, 26. (b) Recent
Advances in the Chemistry of Insect Control; James, N. F.,
Ed.; RCS: London, 1985, 73. (c) Recent Advances in the
Chemistry of Insect Control; James, N. F., Ed.; RCS:
London, 1985, 33. (d) Suckling, C. J. Angew. Chem., Int.
Ed. Engl. 1988, 27, 537.
(4) Anticancer Agents from Natural Products; Cragg, G. M.;
Kingston, D. G. I.; Newman, D. J., Eds.; CRC Press: Boca
Raton, 2005, 402.
H
BnO
(5) RadhaKrishna, P.; Krishnarao, L.; Kannan, V. Tetrahedron
COOEt
7 H
3
H
O
Lett. 2004, 45, 7847.
(6) Navak, S. K.; Thijs, L.; Zwanenburg, B. Tetrahedron Lett.
1999, 40, 981.
(7) (a) Greenberg, A.; Liebman, J. F. In Strained Organic
Molecules; Academic Press: New York, 1978. (b) Wieberg,
K. B. Angew. Chem., Int. Ed. Engl. 1986, 25, 312.
(8) (a) Bartell, L. S.; Carrol, B. L.; Guillory, J. P. Tetrahedron
Lett. 1964, 705. (b) Ono, S.; Shuto, S.; Matsuda, A.
Tetrahedron Lett. 1996, 37, 221.
(9) (a) Radha Krishna, P.; Sharma, G. V. M. Mini-Rev. Org.
Chem. 2006, 3, 137. (b) Radha Krishna, P.;
Rachna Sachwani Srinivas Reddy, P. Synlett 2008, 2897.
(10) Label, H.; Marcoux, J. F.; Molinaro, C.; Charette, A. B.
Chem. Rev. 2003, 103, 977.
(11) (a) Singh, A. K.; Rao, M. N.; Simpson, J. H.; Li, W.-S.;
Thornton, J. E.; Kuehner, D. E.; Kacsur, D. J. Org. Process
Res. Dev. 2002, 6, 618. (b) Delhaye, L.; Merschaert, A.;
Delbeke, P.; Briône, W. Org. Process Res. Dev. 2007, 11,
689.
(R)-MPA
MeO
2'
EDCI, DMAP
CH2Cl2, r.t.
O
6
4a
H
O
BnO
COOEt
7 H
MeO
(S)-MPA
H
EDCI, DMAP
CH2Cl2, r.t.
O
7
Scheme 4 MPA esters of 4a
(12) (a) Tokunaga, M.; Larrow, J. F.; Jacobsen, E. N. Science
1997, 277, 936. (b) Schaus, S. E.; Brandes, B. D.; Larrow,
J. F.; Tokunaga, M.; Hansen, K. B.; Gould, A. E.; Furrow,
M. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 1307.
(13) General Experimental Procedure
Interestingly, extending the analogy, the cis-2,3-cyclopro-
panecarbaldehydes presumably afford similar selectivi-
ties as the alkoxy bearing substrates 1e–h screened in the
present study due to the related transition-state conforma-
tional preferences.
To a cold solution (0 °C) of cyclopropanecarbaldehyde (1.0
mmol) in DMSO were added DABCO (0.5 mmol) and the
activated alkene (1.5 mmol) and the reaction mixture stirred
for 12–15 h at r.t. After completion of reaction (by TLC), the
reaction mixture was partitioned between Et2O (2 × 50 mL)
In conclusion, trans-(2R,3R)-cyclopropanecarbaldehydes
were used for the first time as electrophiles in a diastereo-
selective Baylis–Hillman reaction to afford the corre-
Synlett 2009, No. 16, 2605–2608 © Thieme Stuttgart · New York

2608
P. Radha Krishna
LETTER
and H2O (1 × 60 mL). The organic phase was washed with
brine (2 × 50 mL), dried (Na2SO4), and evaporated under
reduced pressure. The residue was purified by column
chromatography to afford products 4a–h and 5a–h in good
yields (75–85%).
CHCl3). 1H NMR (200 MHz, CDCl3): d = 6.23 (s, 0.15 H),
6.18 (s, 0.85 H), 6.09 (d, 0.15 H, J = 2.9 Hz), 5.96 (d, 0.85
H, J = 3.9 Hz), 5.82 (s, 0.15 H), 5.78 (s, 0.85 H), 5.0 (t, 0.15
H, J = 6.2 Hz), 4.86 (t, 0.85 H, J = 6.6 Hz), 4.21 (q, 2 H,
J = 7.0 Hz), 3.99 (q, 2 H, J = 3.1 Hz), 3.51 (s, 0.85 Hz), 3.34
(s, 0.15 H), 2.15–1.87 (m, 2 H), 1.50–1.45 (m, 2 H), 1.40–
1.25 (m, 9 H). 13C NMR (75 MHz, CDCl3): d = 167.3, 131.5,
127.2, 105.8, 105.5, 105.3, 86.1, 86.0, 85.8, 85.2, 81.4, 71.9,
58.1, 57.2, 36.4, 35.3, 26.8, 26.3, 26.1. HPLC column:
Waters HRC18, 300 × 309 mm, 6 mm, 50% MeCN in H2O,
flow rate: 1 mL/min, tR(major) = 4.496 min, tR(minor) =
8.199 min. IR (neat): 3447, 2924, 2854, 1718, cm–1; ESI-
MS: m/z = 341 [M – H]+,381 [M + 39]+. Anal. Calcd (%) for
C17H26O7: C, 59.64; H, 7.65. Found: C, 59.70; H, 7.58.
(15) (a) Kazuta, Y.; Yamamoto, T.; Matsuda, A.; Shuto, S.
Tetrahedron 2004, 60, 6689. (b) Reetz, M. T.; Kessler, K.;
Schidtberger, S.; Westermann, J.; Steinback, R. Angew.
Chem. 1983, 22, 989.
(14) Spectral Data of Selected Compounds
Compound 4a: thick yellow syrup; [a]D25 +1.07 (c 1.55,
CHCl3). 1H NMR (200 MHz, CDCl3): d = 7.31–7.25 (m, 5
H), 6.21 (s, 0.95 H), 6.15 (s, 0.05 H), 5.83 (s, 0.95 H), 5.80
(s, 0.05 H), 4.46 (s, 2 H), 4.37 (dd, 1 H, J = 4.0, 8.0 Hz), 4.21
(q, 2 H, J = 7.3 Hz), 3.42 (t, 2 H, J = 6.5 Hz), 2.55 (t, 1 H,
J = 6.5 Hz), 2.39 (t, 1 H, J = 7.3 Hz), 2.06–1.71 (m, 1 H),
1.56 (q, 2 H, J = 6.5 Hz), 1.36–1.21 (m, 15 H). 13C NMR (75
MHz, CDCl3): d = 164.1, 142.3, 138.6, 128.2, 127.5, 127.3,
124.8, 72.7, 70.6, 70.4, 60.7, 42.8, 38.8, 31.8, 29.2, 29.1,
26.0, 24.4, 23.8, 14.0. HPLC column: Waters HRC18, 300 ×
309 mm, 6 mm, 50% MeCN in H2O, flow rate: 1 mL/min,
tR(major) = 2.783 min, tR(minor) = 3.639 min. IR (neat):
3440, 2928, 2855, 1716 cm–1. ESI-MS: m/z = 400 [M – H]+,
441 [M + 39]+. Anal. Calcd (%) for C25H34O4: C, 74.59; H,
9.51. Found: C, 74.61, H, 9.50.
(16) Seco, J. M.; Quinoa, E.; Riguera, R. Chem. Rev. 2004, 104,
17.
(17) Seo, Y.; Cho, K. W.; Rho, J.-R.; Shin, J.; Kwon, B.-M.; Bok,
S.-H.; Song, J.-I. Tetrahedron 1996, 52, 10583.
Compound 4g: colorless syrup; [a]D25 –109.1 (c 0.85,
Synlett 2009, No. 16, 2605–2608 © Thieme Stuttgart · New York