Remarkably chemoselective reduction of unmodified Baylis-Hillman adducts by InCl3/NaBH4: Application to the stereoselective synthesis of trisubstituted alkenones including two alarm pheromones

Article abstract of DOI:10.1055/s-2006-947354

A novel, convenient and solely stereoselective synthesis of trisubstituted E-alkenones has been achieved by InCl₃/NaBH₄ mediated chemoselective reduction of unmodified Baylis-Hillman adducts derived from vinyl ketones and cycloalkenones for the first time. The efficiency of this methodology in the practical synthesis of (S)-(+)-manicone and (S)-(+)-normanicone, two alarm pheromones of Manica ants, has been demonstrated. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-947354

LETTER
1879
Remarkably Chemoselective Reduction of Unmodified Baylis–Hillman
Adducts by InCl /NaBH : Application to the Stereoselective Synthesis of
3
4
1
Trisubstituted Alkenones Including Two Alarm Pheromones
C
B
hemoselective
R
i
educti
s
onof
U
nm
w
odified
B
aylis–H
a
illman
A
dd
n
ucts ath Das,* Joydeep Banerjee, Nikhil Chowdhury, Anjoy Majhi, Harish Holla
Organic Chemistry Division I, Indian Institute of Chemical Technology, Hyderabad, 500 007, India
Fax +91(40)7160512; E-mail: biswanathdas@yahoo.com
Received 30 March 2006
tions of Baylis–Hillman adducts 1, we herein report a
novel and convenient synthesis of trisubstituted E-alk-
Abstract: A novel, convenient and solely stereoselective synthesis
of trisubstituted E-alkenones has been achieved by InCl /NaBH
mediated chemoselective reduction of unmodified Baylis–Hillman
3
4
enones 2 via the InCl /NaBH mediated chemoselective
3
4
adducts derived from vinyl ketones and cycloalkenones for the first reduction of these adducts (derived from vinyl ketones
time. The efficiency of this methodology in the practical synthesis and cyclo alkenones) for the first time (Scheme 1). We
of (S)-(+)-manicone and (S)-(+)-normanicone, two alarm phero- also describe the application of this methodology for the
mones of Manica ants, has been demonstrated.
synthesis of (S)-(+)-manicone and (S)-(+)-normanicone
Key words: unmodified Baylis–Hillman adduct, chemoselectivity, (Figure 1).
stereoselectivity, a,b-unsaturated ketones, insects’ pheromones
OH
H
O
O
R1
R3
InCl3/NaBH4
MeCN, r.t.
R1
R3
The trisubstituted alkenone moiety is an important and
key structural unit present in various biologically active
molecules and has been used as a versatile intermediate
R2
R2
3–3.5 h
1
2
–5
2
for the synthesis of various natural products. 3-Alke-
nyl-2-ketones as well as 4-alkenyl-3-ketones are common
metabolites in insects and other arthropods where they
serve a range of communicatory and ecological func-
1
R = aryl, alkyl
5
4–84%
2
R = H, alkyl
1
00% E-selectivity
3
R = alkyl
6
Scheme 1
tions. For example, (4E,6S)-(+)-4,6-dimethyloct-4-ene-
3
-one (manicone) was identified as the mandibular gland
alarm pheromone of two North-American ant species, The Baylis–Hillman reaction is well known for the syn-
7
Manica mutica and Manica bradley while (3E,5S)-(+)- thesis of the stereodefined a,b-unsaturated carbonyl func-
3
,5-dimethylhept-3-ene-2-one (normanicone) as another tionalities present as the central structural unit in a broad
major mandibular gland constituent in the species Manica spectrum of natural products including several alka-
8
13
14
15
11a,16
rubida (Figure 1).
loids, terpenoids, macrolides and pheromones.
It
is noteworthy that Baylis–Hillman adducts derived from
acrylate esters or acrylonitriles and their modified ver-
sions (acetyl and allyl bromide derivatives) have widely
been exploited under various reaction conditions for the
H
O
H
O
H
H
1
1a,16c
synthesis of stereodefined trisubstituted alkenals,
(
S)-(+)-Manicone
(S)-(+)-Normanicone
1
1c,17
16d,18
alkenoates,
triles.
alkenoic acids
and alkeneni-
Figure 1
11c,19
Though synthesis of a wide range of trisubsti-
tuted alkenes from Baylis–Hillman adducts has been well
The physiological properties of these substrates are re- documented in the literature,9b no application of this
markably dependent on the stereochemistry of the double methodology for synthesizing stereodefined trisubstituted
bond present in the molecules.4 An important process for alkenones utilizing Baylis–Hillman adducts has yet been
the synthesis of these compounds was envisaged via reported despite its huge potential to afford this class of
,5
9
application of the Baylis–Hillman reaction. The Baylis– compounds. Only one report of the preparation of trisub-
Hillman reaction is a versatile atom economic reaction stituted Z-alkenones (only two examples)19 from acetyl
producing an interesting class of densely functionalized derivatives of the adducts has been appeared earlier. Thus,
molecules 1 (commonly known as adducts, Scheme 1). As being intrigued with the deficiency of a suitable method of
a part of our continued interest10–12 in synthetic applica- preparing trisubstituted E-alkenones from Baylis–Hill-
man adducts, we realized that a chemoselective reduction
of 1, leaving the keto functionality intact, would result in
SYNLETT 2006, No. 12, pp 1879–1882
Advanced online publication: 24.07.2006
0
1
.0
8
.2
0
0
6
an efficient protocol.
DOI: 10.1055/s-2006-947354; Art ID: D09506ST
©
Georg Thieme Verlag Stuttgart · New York

1
880
B. Das et al.
LETTER
The selective reduction of one functional group in a mol- important for achieving optimum yields: the addition of
ecule containing a number of similar reducible functional- the adduct 1c to InCl /NaBH in MeCN was preferred in
3
4
ities is a challenging problem in organic synthesis. Thus terms of yields of the product as the addition of the reagent
the reduction of Baylis–Hillman adduct 1 into 2 is very to 1c or simultaneous addition of 1c/NaBH /InCl resulted
4
3
complicated because of the presence of two reducible in the recovery of 2c in lower amounts. In absence of
positions (vinylic double bond and keto group) in the ad- InCl the reaction did not proceed chemoselectively. It
3
2
1
duct as well as in the corresponding reduced product may be speculated that chloroindium hydride (Cl InH)
Scheme 1). Moreover, it has been reported that the ester formed by the combination of NaBH and InCl might be
functionality (when R = OMe in 1) of the adduct derived the active species responsible for the reduction. AlCl3/
2
2
0
(
4 3
3
from acrylate ester could even be prone to reduction due NaBH system underwent vigorous reaction with the ad-
4
to the influence of the proximal secondary hydroxyl duct 1c to furnish a complex mixture of products and thus
group. Thus, it is a further challenging task to keep the ke- this reducing system was not useful for the present con-
tone group intact in the reduction of Baylis–Hillman ad- version. The inefficiency of Zn/NH Cl, In/NH Cl, Zn/Cu
4
4
duct 1 containing a keto and hydroxyl group in close couple and Mg to transform adduct 1c into corresponding
proximity. Being familiar with the metal chloride/NaBH product 2c, without promoting side reactions, further
4
1
1c
reagent systems from our earlier study, we initiated our emphasized the distinctive properties of the InCl -NaBH4
present investigation on the reduction of 1c (R = Ph, reagent. The use of this reagent was reported earlier to re-
3
1
2
3
R = H, R = Et) with a combination of NaBH and differ- duce the conjugated double bond of a,b,g,d-unsaturated
4
ent metal chlorides along with various other reducing sys- carbonyl compounds.21
tems to examine the yield of the product 2c (Table 1).
The stereochemistry of the product 2c was found to be
1
13
It was observed that InCl /NaBH in MeCN (entry 5, solely E as determined by comparing the H NMR,
C
3
4
2
2
Table 1) acted as the best catalyst to afford the desired NMR and IR data with that reported previously. This
product 2c in high yield (84%) within 3 hours. Solvents was further confirmed by the aid of H NOESY experi-
1
exerted a remarkable influence on the reduction of the ad- ments. Encouraged by this fact, a series of trisubstituted
duct as in MeOH (entry 4, Table 1) the reaction formed alkenones were prepared from the Baylis–Hillman ad-
several by products while in THF (entry 6, Table 1) the ducts 1 (derived from vinyl ketones and cyclo alkenones)
23
yield of 2c was low (52%).
by treatment with InCl /NaBH in MeCN. The reduction
3 4
was complete within 3–3.5 hours at room temperature.
The trisubstituted alkenones 2 were formed in high yields
In fact, in protic solvents (e.g. MeOH), fast decomposition
of NaBH made the reaction vigorous and uncontrolled.
4
(
Table 2).
The mode of addition of the reactants was also found to be
1
2
3
Table 1 Reduction of 1c (R = Ph, R = H, R = Et) with Different Reducing Systems
Entry
Reagent
Solvent
Time (h)
Isolated yield of 2c
%)
(
1
2
3
4
5
6
7
8
9
NaBH /CuCl ·2H O
MeOH
MeOH
MeOH
MeOH
MeCN
THF
0.4
0.4
0.4
0.4
3
12
4
2
2
NaBH /CoCl ·6H O
27a
4
2
2
NaBH /NiCl ·6H O
32a
4
2
2
NaBH /InCl
43a
4
3
NaBH /InCl (cat.)
84b
4
3
NaBH /InCl (cat.)
3
52b
4
3
Zn/NH Cl (sat.)
H O
14
9
50a,c,d
38a,c,d
35e
4
2
In/NH Cl
EtOH–H O (1:1)
4
2
Zn/HOAc
Mg
CH Cl
4
2
2
1
1
0
1
MeOH
4
22a
Zn/Cu couple
MeOH–H O (3:1)
3
36a,c
2
a
b
c
d
e
More than two unidentified side products were obtained.
Only trisubstituted E-alkenone was obtained.
Reaction mixture was refluxed.
E/Z ratio was 60:40.
E/Z ratio was 51:49.
Synlett 2006, No. 12, 1879–1882 © Thieme Stuttgart · New York

LETTER
Chemoselective Reduction of Unmodified Baylis–Hillman Adducts
1881
a
Table 2 Synthesis of Trisubstituted E-Alkenones 2 by InCl /NaBH
3
4
Entry
R1
R2
R3
Et
Et
Et
Et
Time (h)
Isolated yield (%)
a
b
c
d
e
f
Et
H
3
72
75
84
80
54
57
77
73
i-Pr
Ph
H
3
H
3
2-ClC H
H
3.5
3
6
4
i-Pr
-(CH ) -
2
3
Ph
-(CH ) -
3
2
3
g
(S)-MeCH CHMe-
H
H
Et
3
2
h
(S)-MeCH CHMe-
Me
3
2
a
The structures of the compounds 2 were determined from their spectral (IR, H NMR, 13C NMR and MS) data; E-stereochemistry was assigned
1
1
on the basis of the chemical shift value of the vinylic proton in H NMR spectra.
The formation of stereodefined E-alkenones in the present cone] in 77% and 73% yields, respectively (Table 2), with
reaction can possibly be explained by considering the high optical purities. Our spectral and optical data of these
transition-state models I and II (Figure 2). The transition compounds are in agreement with the literature values.5
a
3
state I is more favored than II since -COR is bulkier than
2
1
the -CH R group and creates more steric crowding to R
2
OH
H
O
InCl /NaBH
MeCN, r.t.
O
group. Moreover, InCl may further stabilize the transi-
3
4
3
tion state I through chelation (forming a six-membered
R
R
1
1a
ring system depicted in model III) and thus allowing
equilibrium to the thermodynamically more favorable E-
isomer.
H
3 h
H
1g R = Et
2g R = Et
2h R = Me
1h R = Me
Scheme 2 Synthesis of pheromones 2g,h
R1
OH
R1
H
H
Rxn
–
–
R3
R2
H
COR3
In conclusion, we have developed a general and efficient
methodology for the stereoselective synthesis of trisub-
stituted E-alkenones from Baylis–Hillman adducts using
InCl /NaBH as a chemoselective reducing agent. The no-
C
COR3
O
R2
R2
Rxn
-
Rxn
Cl
R1
OH
HO
In
3
4
Cl
I
II
III
table feature of this protocol is the mild reaction condi-
tions, operational simplicity, high yields, remarkable
chemoselectivity and sole stereoselectivity. The method
has successfully been applied for the synthesis of some
naturally occurring pheromones. The reducing system,
InCl /NaBH has also been utilized here for the first time
Figure 2
Thus, exclusive E-stereochemistry of the products in-
spired us to select (+)-manicone and (+)-normanicone
Figure 1) as the synthetic targets applying our present
methodology. The Baylis–Hillman adducts 1g and 1h
have been prepared by the treatment of (S)-2-
3
4
(
for the synthesis of a,b-unsaturated ketones.
2
Acknowledgement
methylbutyraldehyde with ethyl vinyl ketone and methyl
vinyl ketone, respectively, according to the literature for
The authors thank CSIR and UGC, New Delhi for financial assi-
2
4
the asymmetric Baylis–Hillman reaction. Both the ad- stance.
ducts were obtained as the inseparable mixtures of two
diastereoisomers (syn:anti). It was expected that, the re-
duction of the adducts 1g,h with the migration of double
bond and subsequent elimination of hydroxyl group
would lead to collapse the stereogenic centers C(5) in 1g
and C(4) in 1h (Scheme 2). Hence, no attempt was made
to separate the diastereoisomers. Thus the chemoselective
reduction of the adducts, 1g and 1h (Scheme 2) with
References and Notes
(1) IICT communication No. 060622. Part 80 in the series
Studies on Novel Synthetic Methodologies’.
‘
(
(
2) Rossi, R.; Carpita, A.; Cossi, P. Tetrahedron 1992, 48, 8801.
3) Jarvis, A. P.; Leibig, J.; Holldobler, B.; Oldham, N. J. Chem.
Commun. 2004, 1196.
(
4) (a) Katzenellenbogen, J. A.; Utawanit, T. J. Am. Chem. Soc.
1974, 96, 6153. (b) Kocienski, P. J.; Ansell, J. N.; Ostrow,
R. W. J. Org. Chem. 1976, 41, 3625.
InCl -NaBH in MeCN at room temperature for three
3
4
hours afforded 2g [(+)-manicone] and 2h [(+)-normani-
Synlett 2006, No. 12, 1879–1882 © Thieme Stuttgart · New York

1
882
B. Das et al.
LETTER
(
5) (a) Martischonok, V.; Melikyan, G. G.; Mineif, A.;
completion (3–3.5 h), the reaction mixture was quenched
Vostrowsky, O.; Bestmann, H. J. Synthesis 1991, 560.
with Et O (25 mL). After the mixture settled, the supernatant
2
(b) De Kimpe, N.; Aelterman, W. Tetrahedron 1996, 52,
organic layer was decanted and the residual semi-solid mass
12815.
(inorganic part) was further extracted with Et O. The
2
(
(
(
6) Blum, M. S. Chemical Defenses of Arthropods; Academic
Press: New York, 1981, 138.
7) Fales, H. M.; Blum, M. S.; Crewe, R. M.; Brand, J. M. J.
Insect Physiol. 1972, 18, 1077.
8) (a) Bestmann, H. J.; Attygalle, A. B.; Glasbrenner, J.;
Riemer, R.; Vostrowsky, O. Angew. Chem., Int. Ed. Engl.
combined ether extract was washed with brine, dried
(Na SO ), and concentrated to obtain the crude product,
2
4
which was purified by column chromatography over silica
1
gel to furnish the pure E-alkenone 2. The spectral (IR, H
1
3
NMR and C NMR and MS) data of some repesentative
adducts and E-alkenones are given bellow.
1
987, 26, 784. (b) Bestmann, H. J.; Attygalle, A. B.;
Compound 1d: IR (KBr): 3474, 1707, 1678, 1442, 1032
–
1 1
Glasbrenner, J.; Riemer, R.; Vostrowsky, O.; Constantino,
M. G.; Melikyan, G.; Morgan, E. D. Liebigs Ann. Chem.
cm . H NMR (300 MHz, CDCl ): d = 7.61 (1 H, dd,
3
J = 8.0, 2.0 Hz), 7.38–7.17 (3 H, m), 6.12 (1 H, s), 5.94 (1 H,
d, J = 3.5 Hz), 5.56 (1 H, s), 3.48 (1 H, d, J = 3.5 Hz), 2.75
1
988, 55.
9) (a) Baylis, A. B.; Hillman, M. E. D. German Patent 2155113,
972; Chem. Abstr. 1972, 77, 34174q. (b) Basavaiah, D.;
1
3
(
(2 H, q, J = 7.0 Hz), 1.11 (3 H, t, J = 7.0 Hz). C NMR (75
1
MHz, CDCl ): d = 203.1, 150.0, 141.8, 128.5, 127.5, 126.8,
3
+
Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811;
125.0, 72.7, 32.0, 8.2. LSIMS (FAB): m/z = 249, 247 [M +
and references cited therein.
Na].
(
(
10) (a) Das, B.; Banerjee, J.; Ravindranath, N.; Venkataiah, B.
Tetrahedron Lett. 2004, 45, 2425. (b) Das, B.; Banerjee, J.;
Ravindranath, N. Tetrahedron 2004, 60, 8357.
Compound 1g: syn:anti = 70:30. IR (KBr): 3418, 1708,
–
1 1
1682, 1463, 1379 cm . H NMR (300 MHz, CDCl ): d
3
(syn) = 6.10 (1 H, s), 5.91 (1 H, s), 4.31 (1 H, t, J = 5.5 Hz),
2.78–2.65 (3 H, m), 1.77–1.52 (3 H, m), 1.12 (3 H, t, J = 7.0
Hz), 0.90 (3 H, t, J = 7.0 Hz), 0.82 (3 H, d, J = 7.0 Hz); d
(anti) = 6.08 (1 H, s), 5.87 (1 H, s), 4.05 (1 H, t, J = 7.0 Hz),
2.78–2.65 (1 H, merged with the signals for anti), 2.38 (2 H,
q, J = 7.0 Hz), 1.49–1.33 (3 H, m), 1.12 (3 H, t, J = 7.0 Hz),
11) (a) Das, B.; Banerjee, J.; Mahender, G.; Majhi, A. Org. Lett.
2004, 6, 3349. (b) Das, B.; Mahender, G.; Chowdhury, N.;
Banerjee, J. Synlett 2005, 1000. (c) Das, B.; Banerjee, J.;
Majhi, A.; Mahender, G. Tetrahedron Lett. 2004, 45, 9225.
12) Das, B.; Majhi, A.; Banerjee, J.; Chowdhury, N.;
Venkateswarlu, K. Chem. Lett. 2005, 34, 1492.
(
(
(
1
3
0.90 (3 H, t, J = 7.0 Hz), 0.78 (3 H, d, J = 7.0 Hz). C NMR
13) Drewes, S. E.; Emslie, N. D. J. Chem. Soc., Perkin Trans. 1
(75 MHz, CDCl ): d (syn) = 202.8, 149.8, 124.7, 75.1, 39.4,
3
1
982, 2089.
14) (a) Jenn, T.; Heissler, D. Tetrahedron 1998, 54, 97.
b) Grassi, D.; Lippuner, V.; Aebi, M.; Brunner, J.; Vasella,
32.0, 26.8, 13.0, 12.1, 8.1; d (anti) = 203.7, 149.0, 125.0,
77.4, 39.8, 32.0, 24.9, 16.3, 11.9, 8.1. LSIMS (FAB): m/z =
+
(
193 [M + Na].
A. J. Am. Chem. Soc. 1997, 119, 10992. (c) Hoffmann, H.
M. R.; Rabe, J. J. Org. Chem. 1985, 50, 3849.
Compound 1h: syn:anti = 60:40, IR (KBr): 3418, 1714,
–
1 1
1675, 1460, 1367 cm . H NMR (300 MHz, CDCl ): d
3
(
(
15) Roush, W. R.; Brown, B. B. J. Org. Chem. 1993, 58, 2151.
16) (a) Das, B.; Chowdhury, N.; Banerjee, J.; Majhi, A.;
Mahender, G. Chem. Lett. 2006, 35, 358. (b) Mateus, C. R.;
Feltrin, M. P.; Costa, A. M.; Cohello, F.; Almedia, W. P.
Tetrahedron 2001, 57, 6901. (c) Basavaiah, D.; Hyma, R. S.
Tetrahedron 1996, 52, 1253. (d) Fernandes, L.; Bortoluzzi,
A. J.; Sa’, M. M. Tetrahedron 2004, 60, 9983.
(syn) = 6.12 (1 H, s), 5.97 (1 H, s), 4.32 (1 H, d, J = 5.5 Hz),
2.36 (3 H, s), 2.19 (1 H, d, J = 3.5 Hz), 1.72–1.54 (2 H, m),
1.22–1.16 (1 H, m), 0.99–0.87 (6 H, m); d (anti) = 6.11 (1 H,
s), 5.92 (1 H, s), 4.08 (1 H, d, J = 7.0 Hz), 2.36 (3 H, s), 2.19
(1 H, br s), 1.46–1.32 (2 H, m), 1.18–1.07 (1 H, m), 0.85–
1
3
0.77 (6 H, m). C NMR (75 MHz, CDCl ): d (syn) = 201.0,
3
150.0, 126.0, 75.1, 39.2, 30.0, 26.9, 14.0, 12.2; d (anti) =
(
(
(
17) (a) Shadakshari, U.; Nayak, S. K. Tetrahedron 2001, 57,
201.4, 149.8, 126.5, 77.5, 39.8, 30.0, 25.0, 16.5, 12.0.
+
4599. (b) Li, J.; Qian, W.; Zhang, Y. Tetrahedron 2004, 60,
LSIMS (FAB): m/z = 179 [M + Na].
5793.
Compound 2b: IR (KBr): 1718, 1672, 1462, 1373, 1219
–
1 1
18) Basavaiah, D.; Krishnamacharyulu, M.; Hyma, R. S.;
cm . H NMR (300 MHz, CDCl ): d = 6.36 (1 H, d, J = 7.0
3
Sarma, P. K. S.; Kumaragurabaran, N. J. Org. Chem. 1999,
6
Hz), 2.70 (1 H, m), 2.68 (2 H, q, J = 7.0 Hz), 1.78 (3 H, s),
1.10–1.02 (9 H, m) Hz). C NMR (75 MHz, CDCl3):
1
3
4, 1197.
19) Pachamuthu, K.; Vankar, Y. D. Tetrahedron Lett. 1998, 39,
439.
d = 202.5, 148.8, 134.7, 30.2, 28.6, 22.4, 11.6, 8.9. LSI-MS
+
5
(FAB): m/z = 163 [M + Na].
(
(
(
20) Patra, A.; Batra, S.; Bhaduri, A. P. Synlett 2003, 1611.
21) Ranu, B. C.; Samanta, S. J. Org. Chem. 2003, 68, 7130.
22) Yanagisawa, A.; Goudu, R.; Arai, T. Org. Lett. 2004, 6,
Compound 2d: IR (KBr): 1718, 1675, 1630, 1468, 1438,
–
1 1
1363 cm . H NMR (300 MHz, CDCl ): d = 7.59 (1 H, s),
3
7.42 (1 H, m), 7.36–7.27 (3 H, m), 2.85 (2 H, q, J = 7.0 Hz),
1
3
4281.
1.92 (3 H, s), 1.19 (3 H, t, J = 7.0 Hz). C NMR (75 MHz,
(
23) General Procedure for the Reduction of Adducts.
CDCl ): d = 202.6, 137.8, 135.6, 134.98, 134.92, 130.5,
3
To a stirred solution of InCl (90 mg, 0.4 mmol) and NaBH
129.9, 128.2, 126.6, 30.1, 13.8, 8.7. LSIMS (FAB): m/z =
3
4
+
(
168 mg, 4.5 mmol) in dry MeCN (10 mL) was added a
209 [M + 1], 211.
solution of Baylis–Hillman adduct 1 (3 mmol) in MeCN (4
mL) at r.t. under nitrogen atmosphere. Stirring was
continued and the reaction was monitored by TLC. After
(24) Radhakrishna, P.; Manjuvani, A.; Rajaskhar, E. ARKIVOC
2005, (iii), 99.
Synlett 2006, No. 12, 1879–1882 © Thieme Stuttgart · New York