Studies towards the total synthesis of (-)-borrelidin: a strategy for the construction of the C11-C15 cyanodiene fragment and the utility of RCM for macrocyclization using model systems

Article abstract of DOI:10.1016/j.tetlet.2006.06.092

We report here a methodology for the construction of a conjugated cyanodiene synthon and the propensity of such synthons to participate in the olefin metathesis reaction. To this end, we have developed a strategy for the construction of the C11-C15 fragme

Full text of DOI:10.1016/j.tetlet.2006.06.092

Tetrahedron Letters 47 (2006) 6103–6106
Studies towards the total synthesis of (ꢀ)-borrelidin: a strategy
for the construction of the C11–C15 cyanodiene fragment and
the utility of RCM for macrocyclization using model systemsI
C. Vamsee Krishna,a,b Santanu Maitra,a R. Vasu Dev,a K. Mukkantib and Javed Iqbala,*
aDiscovery Research, Dr. Reddy’s Laboratories, Ltd, Miyapur, Hyderabad 500049, AP, India
bChemistry Division, Institute of Science and Technology, JNT University, Kukatpally, Hyderabad 500072, AP, India
Received 20 April 2006; revised 5 June 2006; accepted 15 June 2006
Available online 10 July 2006
Abstract—We report here a methodology for the construction of a conjugated cyanodiene synthon and the propensity of such syn-
thons to participate in the olefin metathesis reaction. To this end, we have developed a strategy for the construction of the C11–C15
fragment of borrelidin and demonstrated the utility of the RCM reaction in the preparation of the final macrolide. To our knowl-
edge, this is the first example of a RCM with a nitrile functionality on a diene.
Ó 2006 Elsevier Ltd. All rights reserved.
Borrelidin1 was shown to be an 18-membered macrolide
distinguished by a 1,3,5,7-‘skipped’ methylene chain
(C4–C10), a cyclopentane carboxylic acid fragment
and a conjugated cyanodiene unit and has attracted
the attention of several synthetic groups around the
world2 (Fig. 1).
to synthesize this complex macrolide, we envisioned a
strategy employing the versatile RCM or cross-metathe-
sis reaction involving a conjugated cyanodiene synthon
to construct the final macrolide.
Even though RCM reactions on conjugated dienes and
their utility in macrolide construction are known,3 ring
closing metathesis/cross-metathesis of a conjugated
cyanodiene is unprecedented. A literature search re-
vealed a rather interesting pattern, indeed the striking
power of RCM methodology is reflected in the synthesis
of heterocycles,4 lactones,5 sulfones6 and sulfonamides.7
The involvement of a,b-unsaturated esters in RCM and
cross-metathesis are numerous,8 in contrast, no exam-
ples of a,b-unsaturated nitriles in RCM have been
reported, even when the cyano functionality is situated
at the terminus of the diene,9 the only exception being
a cross-metathesis involving acrylonitrile.10 We initially
wanted to test the feasibility of our hypothesis in appro-
priate model systems due to these limited results.
The conjugated cyanodiene unit is unprecedented in nat-
ural product structures, and is an essential feature for
the anti-microbial action of borrelidin. In our endeavors
OH
8
6
4
3
10
11
HO
O
1
O
17
18
N
H
COOH
22
The ylide 1 generated from triphenylphosphine and
chloroacetonitrile was treated with bromine in the pres-
ence of sodium hexamethyldisilylamide to give the cor-
responding bromo-ylide 2.11 Ylide 2 was reacted with
E-crotonaldehyde in dichloromethane to afford the
cyanodiene 3 in 58% yield12 as a mixture of isomers.
Reaction of 3 with isopropylmagnesium bromide and
addition of undecylenic aldehyde to the resulting
Figure 1.
Keywords: Borrelidin; Olefin metathesis.
q DRL Publication No. 571-A.
*
Corresponding author. Tel.: +91 40 23045439; fax: +91 40 2304
5438; e-mail: Javediqbaldrf@hotmail.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.092

6104
C. V. Krishna et al. / Tetrahedron Letters 47 (2006) 6103–6106
Grignard product gave a mixture of E,Z (4a) and E,E
(4b) isomers13 in 65% yield (Scheme 1) favouring the
E,E isomer (4b). Compound 4 was subjected to column
chromatography to give the individual isomers 4a and
4b which were characterized by NOE studies.14
diene. Addition of another 5 mol % of the catalyst with
reflux for 28 h increased the amount of dimer. Column
purification gave 5b and 6 with yields of 24% and
22%, respectively, along with 26% of the unreacted diene
(Scheme 3). To our surprise the geometry of the newly
formed double bond was found to be Z from the cou-
pling constant value of 11.0 Hz. No chromatographic
or spectroscopic evidence for the formation of the E iso-
mer was observed.
Compound 4a, when subjected to ring closing metathe-
sis15 with 5 mol % of Grubbs’ II catalyst in refluxing
dichloromethane (0.6 mM with respect to substrate)
for 18 h, gave the macrocycle 5a and unreacted starting
material as observed on TLC. Addition of another
5 mol % of the catalyst and refluxing for 28 h afforded,
exclusively, 5a16 in a yield of 54% along with a trace
amount of dimer (Scheme 2). The geometry of the newly
formed double bond was deduced to be E from the cou-
pling constant value of 15.6 Hz. No chromatographic or
spectroscopic evidence of the Z isomer was observed.
From this study, it was evident that the geometry of
the conjugated cyanodiene in 5a is Z,E which is in accor-
dance with the geometry in borrelidin.17
Intrigued by the anomalous behaviour of the isomers 4a
and 4b during RCM, we sought to substantiate our find-
ings by studying the NOE interactions in compounds 5a
and 5b. The NOE studies also confirmed the E and Z
geometries. To assess the role of the OH group in these
reactions, the hydroxyl functionality in 4b was oxidized
to a ketone with Dess–Martin reagent. The ring closing
metathesis of this ketone with 15 mol % of Grubbs’ II
catalyst in refluxing dichloromethane (0.5 mM with
respect to substrate) for 52 h proved to be very sluggish.
In contrast, when isomer 4b was subjected to ring clos-
ing metathesis with 5 mol % of Grubbs’ II catalyst in
refluxing dichloromethane (0.6 mM with respect to sub-
strate) for 18 h, formation of both macrocycle 5b18 and
dimer 6 was observed along with unreacted starting
We propose the following models for the contrasting
geometries of the newly formed double bonds during
RCM. In 4a, the Z geometry of the double bond adja-
cent to the cyano group forces the ruthenium complex
on the terminal diene to attack the conjugated double
bond from the top thereby forming the cyclized com-
pound 5a with an E double bond (Fig. 2a). On the other
hand, when the geometry is E (4b), the molecule adopts
a conformation where the ruthenium complex attacks
the conjugated diene from the bottom affording 5b with
a Z double bond (Fig. 2b). Further experiments are
required in order to prove this hypothesis.
CN
(Z)
(E)
Br
Br
a
b
P
P
CN
CN
Br
(E)
(E)
The formation of the dimer as a major product in the
RCM of 4b, even at high dilution, shows the propensity
of this isomer to participate in cross-metathesis more
readily than 4a. Further studies are ongoing in this
direction. The higher catalyst/substrate ratio required
in these reactions may be due to catalyst decomposition
mediated by the nitrile group.10
CN
1
2
3
N
N
(E)
(Z)
(E)
(E)
OH
(CH2)7
OH
c
In conclusion, we have undertaken a study on the ring
closing metathesis of a conjugated cyanodiene. To this
end, we have demonstrated a strategy for building the
Z,E C11–C15 conjugated cyanodiene synthon in borre-
lidin. To our knowledge, this is the first example of a
(CH2)7
4a
4b
Scheme 1. Reagents and conditions: (a) NaN(SiMe3)2, Br2, toluene,
ꢀ78 °C to rt, (72%); (b) E-crotonaldehyde, CH2Cl2, rt, (58%); (c) (i)
i-PrMgBr, THF, ꢀ40 °C, (ii) undecylenic aldehyde, rt, (65% over two
steps).
CN
(E)
CN
(Z)
CN
(E)
OH
a
(E)
OH
OH
+
+ unreacted
starting
material
CN
CN
(CH2)7
(Z)
(Z)
(E)
(E)
OH
OH
(CH2)7
a
+ trace of dimer
4b
5b
HO
NC
4a
5a
6
Scheme 2. Reagents and conditions: (a) Grubbs’ II, catalyst
(10 mol %), CH2Cl2 (0.6 mM), reflux, 28 h (54%).
Scheme 3. Reagents and conditions: (a) Grubbs’ II catalyst
(10 mol %), CH2Cl2 (0.6 mM), reflux, 28 h (5b, 24% and 6, 22%).

C. V. Krishna et al. / Tetrahedron Letters 47 (2006) 6103–6106
6105
Ru
Ru
H
H
H
H
(E)
OH
OH
OH
H
OH
(Z)
H
H
H
H
H
H
N
N
N
N
5a
Figure 2a.
H
N
H
H
N
H
H
N
(Z)
H
N
Ru
(E)
H
OH
H
OH
H
OH
H
OH
H
Ru
5b
Figure 2b.
Stachel, S. J.; Baeschlin, D. K.; Danishefsky, S. J. J. Am.
Chem. Soc. 2001, 123, 10903–10908.
4. Reviews: (a) Pandit, U. K.; Overkleeft, H. S.; Borer, B. C.;
Biera¨ugel, H. Eur. J. Org. Chem. 1999, 9, 959–968; (b)
Philips, A. J.; Abell, A. D. Aldrichimica Acta 1999, 32, 75–
89.
5. (a) Houri, A. F.; Xu, Z.; Cogan, D. A.; Hoveyda, A. H. J.
Am. Chem. Soc. 1995, 117, 2943–2944; (b) Miller, J. F.;
Termin, A.; Koch, K.; Piscopio, A. D. J. Org. Chem. 1998,
63, 3158–3159; (c) White, J. D.; Hrnciar, P.; Yokochi, A.
F. T. J. Am. Chem. Soc. 1998, 120, 7359–7360; (d) Ripka,
A. S.; Bohacek, R. S.; Rich, D. H. Bioorg. Med. Chem.
Lett. 1998, 8, 357–359; (e) Sukkari, H. E.; Gesson, J. P.;
Renoux, B. Tetrahedron Lett. 1998, 39, 4043–4046.
6. (a) Paquette, L. A.; Fabris, F.; Tae, J.; Gallucci, J.;
Hofferberth, J. E. J. Am. Chem. Soc. 2000, 122, 3391–
RCM with a nitrile functionality on a diene. Further
studies are ongoing towards the total synthesis of the
macrolide.
Acknowledgements
We thank Dr. Reddy’s Laboratories for facilities and
funding and the Analytical department, Discovery
Research, Dr. Reddy’s Laboratories for the analytical
support.
References and notes
3398; (b) Furstner, A.; Gastner, T.; Weintritt, H. J. Org.
¨
1. (a) Berger, J.; Jampolsky, L. M.; Goldberg, M. W. Arch.
Biochem. 1949, 22, 476–478; (b) Singh, S. K.; Gurusid-
daiah, S.; Whalen, J. W. Antimicrob. Agents Chemother.
1985, 27, 239–245; Maher, H.; Evans, R. H. J. Antibiot.
1987, 40, 1455–1456.
2. (a) Haddad, N.; Grishko, M.; Brik, A. Tetrahedron Lett.
1997, 38, 6075–6078; (b) Haddad, N.; Brik, A.; Grishko,
M. Tetrahedron Lett. 1997, 38, 6079–6082; (c) Zhao, C. X.;
Duffey, M. O.; Taylor, S. J.; Morken, J. P. Org. Lett. 2001,
3, 1829–1831; (d) Duffey, M. O.; LeTiran, A.; Morken, J.
P. J. Am. Chem. Soc. 2003, 125, 1458–1459; (e) Hanessian,
S.; Yang, Y.; Giroux, S.; Mascitti, V.; Ma, J.; Raeppel, F.
J. Am. Chem. Soc. 2003, 125, 13784–13792; (f) Nagamitsu,
T.; Takano, D.; Fukuda, T.; Otoguro, K.; Kuwajima, I.;
Harigaya, Y.; Omura, S. Org. Lett. 2004, 11, 1865–1867;
(g) Vong, B. G.; Kim, S. H.; Abraham, S.; Theodorakis, E.
A. Angew. Chem., Int. Ed. 2004, 43, 3947–3951.
3. (a) Wagner, J.; Martin Cabrejas, L. M.; Grossmith, C. E.;
Papageorgiou, C. D.; Senia, F.; Wagner, D.; France, J.;
Nolan, S. P. J. Org. Chem. 2000, 65, 9255–9260; (b)
Dvorak, C. A.; Schmitz, W. D.; Poon, D. J.; Pryde, D. C.;
Lawson, J. P.; Amos, R. A.; Meyers, A. I. Angew. Chem.,
Int. Ed. 2000, 39, 1664–1666; (c) Biswas, K.; Lin, H.;
Njardarson, J. T.; Chappell, M. D.; Chou, T. C.; Guan,
Y.; Tong, W. P.; He, L.; Horwitz, S. B.; Danishefsky, S. J.
J. Am. Chem. Soc. 2002, 124, 9825–9832; (d) Wang, X.;
Porco, J. A., Jr. J. Am. Chem. Soc. 2003, 125, 6040–6041;
(e) Malecka, R. E., Jr.; Terell, L. R.; Geng, F.; Ward, J. S.,
III. Org. Lett. 2002, 2841–2844; (f) Garbaccio, R. M.;
Chem. 1999, 64, 2361–2366; (c) Grela, K.; Bieniek, M.
Tetrahedron Lett. 2001, 42, 6425–6428.
7. (a) Paquette, L. A.; Ra, C. S.; Schloss, J. D.; Leit, S. M.;
Gallucci, J. C. J. Org. Chem. 2001, 66, 3564–3573; (b)
Paquette, L. A.; Leit, S. M. J. Am. Chem. Soc. 1999, 121,
8126–8127.
8. (a) Funk, T. W.; Efskind, J.; Grubbs, R. H. Org. Lett.
2005, 7, 187–190; (b) Ghosh, A. K.; Lei, H. J. Org. Chem.
2000, 65, 4779–4781; (c) Ghosh, A. K.; Cappiello, J.; Shin,
D. Tetrahedron Lett. 1998, 39, 4651–4654; (d) Nicolaou,
K. C.; Rodriguez, R. M.; Mitchell, H. J.; Suzuki, H.;
Fylaktakidou, C.; Baudouin, O.; Delft, F. L. Chem. Eur.
J. 2000, 6, 3095–3098; (e) Cossy, J.; Bauer, D.; Bellosta, V.
Tetrahedron Lett. 1999, 40, 4187–4188; (f) Bassindale, M.
J.; Hamley, P.; Leitner, A.; Harrity, J. P. A. Tetrahedron
Lett. 1999, 40, 3247–3250; (g) Furstner, A.; Thiel, O. R.;
¨
Ackermann, L.; Schanz, H. J.; Nolan, S. P. J. Org. Chem.
2000, 65, 2204–2207; (h) Ramachandran, P. V.; Reddy, M.
V. R.; Brown, H. C. Tetrahedron Lett. 2000, 41, 583–586;
(i) Brouard, I.; Hanxing, L.; Martin, J. D. Synthesis 2000,
883–886; (j) Ghosh, A. K.; Bilcer, G. Tetrahedron Lett.
2000, 41, 1003–1006; (k) Greer, P. B.; Donaldson, W. A.
Tetrahedron Lett. 2000, 41, 3801–3803.
9. Basu, K.; Cabral, J. A.; Paquette, L. A. Tetrahedron Lett.
2002, 43, 5453–5456.
10. Crowe, W. E.; Goldberg, D. R. J. Am. Chem. Soc. 1995,
117, 5162–5163.
11. Bestmann, H. J.; Schmidt, M. Angew. Chem., Int. Ed.
Engl. 1987, 26, 79–81.

6106
C. V. Krishna et al. / Tetrahedron Letters 47 (2006) 6103–6106
25
12. Compound 3: E,Z mixture: ½aꢁD ꢀ1.3 (c 1.00, CHCl3); IR
(KBr): 3420, 2923, 2853, 1718, 1502, 1362, 1174, 1118;
Mass (m/z): CI: 173 (M++1, for 81Br); 1H NMR
15. Typical procedure for the RCM reaction: To the starting
diene (4a or 4b) in dry dichloromethane (0.6 mM with
respect to substrate) was added 5 mol % of Grubbs’ II
catalyst (Aldrich) as a solution in dichloromethane. The
contents were refluxed under argon for 18 h and subse-
quently another 5 mol % of the catalyst was added and
refluxing continued for 28 h. Dichloromethane was
removed under reduced pressure and the residue was
purified by column chromatography over 230–400 silica
gel. Elution of the column with 15% ethyl acetate in
hexanes afforded the pure compound as a gummy mass.
16. Compound 5a: IR (KBr): 3421, 2928, 2857, 2214, 1639,
1383, 1190, 1053; ESMS: 220 (M++1), 237 (M++NH4),
456 (2M++NH4); 1H NMR (400 MHz, CDCl3) d 1.10–
2.10 (m, 15H), 2.30–2.40 (m, 2H), 4.80 (dd, 1H,
J = 4.1 Hz, 10.9 Hz), 6.01–6.09 (m, 1H), 6.32–6.39 (dd,
1H, J = 15.3 Hz, 11.0 Hz), 6.85–6.88 (d, 1H, J = 10.7 Hz);
13C (50 MHz, CDCl3) d 24.0, 25.5, 26.5, 26.7, 27.3, 27.8,
33.5, 35.6, 66.6, 115.7, 118.1, 125.6, 143.6, 143.7.
(400 MHz, CDCl3)
d
1.88 (dd, 3H, J = 1.61 Hz,
6.71 Hz), 1.92 (d, 3H, J = 5.4 Hz), 6.17–6.26 (m, 2H),
6.31–6.42 (m, 2H), 7.10–7.13 (d, 1H, J = 11 Hz), 7.16–7.18
(d, 1H, J = 9.4 Hz); 13C (50 MHz, CDCl3) d 18.7, 19.1,
83.8, 85.5, 127.3, 127.5, 141.6, 143.8, 145.7, 149.8.
13. Thibonnet, J.; Vu, V. A.; Berillon, L.; Knochel, P.
Tetrahedron 2002, 58, 4787–4799.
25
14. Compound 4a: ½aꢁD ꢀ0.9 (c 1.00, CHCl3); IR (KBr): 3443,
2927, 2855, 2212, 1640, 1442, 1035; ESMS: 262 (M++1),
279 (M++NH4), 284 (M++Na); 1H NMR (400 MHz,
CDCl3) d 1.20–1.80 (m, 15H), 1.90 (dd, 3H, J = 1.57 Hz,
6.7 Hz), 2.01–2.06 (m, 2H), 4.59–4.61 (m, 1H), 4.90–5.00
(m, 2H), 5.75–5.86 (m, 1H), 6.11–6.19 (m, 1H), 6.30–6.40
(qdd, 1H, J = 1.6 Hz, 11.2 Hz, 14.7 Hz), 6.70 (d, 1H,
J = 11.5 Hz); 13C (50 MHz, CDCl3) d 18.8, 25.2, 28.8,
29.0, 29.2, 29.3, 29.4, 33.7, 36.0, 67.3, 114.1, 114.7, 118.6,
25
125.2, 139.1, 141.2, 144.3. Compound 4b: ½aꢁD 0.6 (c 1.00,
17. Kuo, M. S.; Yurek, D. A.; Kloosterman, D. A. Antibiotics
1989, 1006–1007.
CHCl3); IR (KBr): 3423, 2927, 2855, 2213, 1642, 1443,
1043; ESMS: 262 (M++1), 279 (M++NH4), 284
18. Compound 5b: IR (KBr): 3408, 2928, 2857, 2217, 1631,
1460, 1051; ESMS: 220 (M++1), 237 (M++NH4), 456
(2M++NH4); 1H NMR (400 MHz, CDCl3) d 1.20–1.80
(m, 15H), 2.20–2.30 (m, 2H), 4.35–4.37 (m, 1H), 5.81–5.88
(m, 1H), 6.53–6.58 (t, 1H, J = 11.0 Hz), 7.10 (d, 1H,
J = 11.0 Hz); 13C (50 MHz, CDCl3) d 22.8, 24.5, 25.0,
25.8, 26.5, 26.6, 27.8, 33.5, 73.4, 116.0, 116.6, 125.6, 139.0,
141.3.
(M++Na); H NMR (400 MHz, CDCl3) d 1.20–1.80 (m,
1
15H), 1.90 (dd, 3H, J = 1.6 Hz, 6.9 Hz), 2.01–2.06 (m,
2H), 4.59–4.61 (m, 1H), 4.90–5.0 (m, 2H), 5.70–5.80 (m,
1H), 6.10– 6.19 (m, 1H), 6.40–6.50 (qdd, 1H, J = 1.6 Hz,
11.2 Hz, 15.0 Hz), 6.70 (d, 1H, J = 11.0 Hz); 13C (50 MHz,
CDCl3) d 18.5, 25.2, 28.8, 29.0, 29.2, 29.3, 29.4, 33.7, 36.1,
72.5, 114.0, 114.5, 116.3, 127.8, 139.1, 139.9, 143.8.