Stereoconvergent synthesis of the C1-C11 and C12-C24 fragments of (-)-macrolactin-A

Article abstract of DOI:10.1016/j.tetlet.2007.11.107

Stereoconvergent syntheses of the C1-C11 and C12-C24 fragments of (-)-macrolactin-A are reported.

Full text of DOI:10.1016/j.tetlet.2007.11.107

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 463–466
Stereoconvergent synthesis of the C1–C11 and C12–C24
fragments of (ꢀ)-macrolactin-A
J. S. Yadav *, M. Raj Kumar, G. Sabitha
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 11 July 2007; revised 14 November 2007; accepted 20 November 2007
Available online 23 November 2007
Abstract
Stereoconvergent syntheses of the C1–C11 and C12–C24 fragments of (ꢀ)-macrolactin-A are reported.
Ó 2007 Published by Elsevier Ltd.
Keywords: Macrolactin-A; Macrolide; Fragments; Sharpless asymmetric epoxidation; Sonogashira coupling
Macrolactin-A (1), a 24-membered polyene macrolide,
which was isolated in 1989 by Fenical and co-workers1
from a deep-sea marine bacterium, belongs to the class of
macrolactins whose other members have recently been iso-
lated.2 This compound possesses three 1,3-diene units (Z,E-;
E,Z-; E,E) and four stereogenic centres. It exhibits a broad
spectrum of activity with significant antiviral and cancer
cell cytotoxic properties including inhibition of B16-F10
murine melanoma cell replication (IC50 = 3.5 lg/mL).
Because of its unreliable supply from cell cultures, as well
its structural uniqueness and broad therapeutic potential,
macrolactin-A has been the subject of synthetic studies
by several research groups.3–5
By retrosynthetic analysis, macrolactin-A was discon-
nected into C1–C11 and C12–C24 fragments 2 and 3. In
the forward sense they can be connected by epoxide open-
ing using the Yamaguchi protocol followed by reduction
using Lindlar’s catalyst and macrolactonization. Herein
we report the syntheses of the C1–C11 and C12–C24 frag-
ments using epoxide opening for the introduction of the
stereogenic centres at C7, C13 and C23 (Scheme 1).
The primary hydroxyl group of 3-butyn-1-ol 4 was pro-
tected as its PMB ether 7 using PMB–Br and NaH in 92%
yield. Treatment of ether 7 with EtMgBr and paraformal-
dehyde afforded alcohol 8 in 75% yield. Compound 8 was
converted to the allyl alcohol 9 using LiAlH4 in refluxing
THF in 79% yield. Sharpless asymmetric epoxidation6 of
9 afforded epoxyalcohol 10 in 83% yield (95% ee).7 A Swern
oxidation of compound 10 followed by Wittig olefination
gave the a,b-unsaturated ester 12. Reduction of the ester
group of compound 12 using DIBAL-H at ꢀ100 °C affor-
ded the epoxy allylic alcohol 13 in 65% yield. Compound
13 was converted to the epoxy allylic chloride 14 by treat-
ment with triphenylphosphine, NaHCO3 and CCl4 at reflux
in 77% yield. Treatment of 14 with LiNH2 at ꢀ33 °C or
LDA at ꢀ78 °C gave the hydroxy-enyne 15 in 80% yield.8
The secondary hydroxyl group of 15 was protected as its
silyl ether 16 using TBDMS–Cl and imidazole. Deprotec-
tion of the PMB group of 16 was achieved in the presence
of DDQ9 followed by IBX oxidation to give aldehyde 18. A
two-carbon extension of 18 using triphenylphosphoranyl-
ideneacetaldehyde afforded 19 in 73% yield. Applying the
Stille–Gennari10 reaction to compound 19 completed the
synthesis of the C1–C11 fragment 2 using methyl P,P0-
bis(2,2,2-trifluoroethyl)phosphonoacetate in the presence
of NaH at ꢀ78 °C with excellent stereoselectivity (Z,E/
E,E 95:5) in 80% yield (Scheme 2).
The synthesis of fragment C12–C17 started from the
1,2-protected (R)-1,2,4 butanetriol 20 (synthesized from
(R)-malic acid).11 A one-pot Swern oxidation and Wittig
*
Corresponding author. Tel.: +91 40 27193434; fax: +91 40 27160512.
E-mail address: yadavpub@iict.res.in (J. S. Yadav).
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.11.107

464
J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 463–466
OTBDMS
OH
OH
4
2
1
OMe
O
11
12
O
O
HO
OTBDPS
O
OTBDPS
HO
O
O
OAc
+
Br
(-) -Macrolactin-A
1
PMBO
6
3
5
Scheme 1. Retrosynthetic approach to the total synthesis of macrolactin-A.
c
b
OPMB
OR
HO
OPMB
HO
8
9
4, R =H
7, R = PMB
a
O
d
i
O
f
R
R
OPMB
OPMB
12, R = COOEt
13, R = CH2OH
14, R = CH2Cl
g
h
10, R = CH2OH
11, R = CHO
e
OR1
OTBDMS
O
OTBDMS
l
m
OR2
O
15, R1 = H, R2 = PMB
j
19
18
16, R1 = TBDMS, R2 = PMB
17, R1 = TBDMS, R2 = H
k
OTBDMS
n
2
O
OMe
Scheme 2. Reagents and conditions: (a) NaH, PMB–Br, THF, 0 °C, 6 h, 92%; (b) EtMgBr, (CH2O)n, THF, 3 h, 75%; (c) LiAlH4, THF, reflux, 4 h, 79%;
(d) L-(+)-DET, Ti(OiPr)4, TBHP, DCM, ꢀ20 °C, 6 h, 83%; (e) (COCl)2, DMSO, Et3N, DCM, ꢀ78 °C, 86%; (f) Ph3P@CHCO2Et, C6H6, rt, 12 h, 83%; (g)
DIBAL-H, DCM, ꢀ100 °C, 2 h, 65%; (h) Ph3P, NaHCO3, CCl4, reflux, 4 h, 77%; (i) LiNH2, ꢀ33 °C, 3 h, 80%; (j) TBDMSCl, imidazole, DCM, 0 °C, 2 h,
87%; (k) DDQ, DCM/H2O (9:1), 3 h, 75%; (l) IBX, DCM, 2 h, 73%; (m) Ph3P@CHCHO, DCM, rt, 12 h, 73%; (n) (CF3CH2O)P(O)CH2CO2Me, NaH,
ꢀ78 °C, 2 h, 80%.
olefination of this alcohol gave the a,b-unsaturated ester 21
in 89% yield. DIBAL-H reduction of ester 21 followed by a
Sharpless asymmetric epoxidation gave epoxyalcohol 23
(96% de).12 This was converted to the corresponding
chloride 24 by treatment with triphenylphosphine,
NaHCO3 and CCl4 under reflux. Treatment of chloride
24 with LiNH2 at ꢀ33 °C or with LDA at ꢀ78 °C afforded
the chiral propargyl alcohol 25,13 which upon acetyl-
ation using Ac2O and Et3N gave the desired acetate 5
(Scheme 3).
The synthesis of the C18–C24 fragment started by open-
ing of (R)-propyleneoxide14 26 using alkyne 7 to afford the
secondary alcohol 27 in 76% yield.15 Alcohol 27 was depro-
tected using DDQ followed by selective tosylation in the
presence of TsCl and Et3N at 0 °C to afford tosylate 29
in 88% yield. The tosyl group was then converted to a
methyl group by treatment with LAH at 40 °C. Zipper
isomerization of alkyne 30 in the presence of NaNH2 and
1,3-diaminopropane at 80 °C gave the terminal alkyne 31
in 73% yield.16 Protection of alcohol 31 as its TBDPS ether
32 was achieved using TBDPSCl and imidazole. Stannyl-
ation17 of alkyne 32 using n-Bu3SnH and AIBN at
120 °C followed by treatment with NBS afforded bromide
6 as an inseparable mixture of E and Z isomers in a 4:1
ratio (Scheme 4).18
Vinyl bromide 6 was coupled with alkyne 5 in the pres-
ence of a catalytic amount of Pd(PPh3)4, CuI and diethyl-
amine at rt, to afford enyne 34 as an inseparable mixture
of E and Z isomers (9:1) in 60% yield.19 Methanolysis of
acetate 35 using K2CO3 in MeOH at room temperature,
followed by LAH reduction gave the E isomer 36 (after
separation from its Z isomer). The hydroxyl group of 36
was protected as the PMB ether 37 using PMB–Br and
NaH under reflux. Removal of cyclohexylidene acetal in
37 was achieved with PTSA in MeOH to afford diol 38,
which on tosylation using TsCl, Et3N gave tosylate 39.

J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 463–466
465
O
O
O
O
a
b
c
O
O
O
OEt
OH
OH
20
21
22
O
OAc
O
O
OH
e
f
O
O
O
O
R
5
25
23, R = CH2OH
24, R = CH2Cl
d
Scheme 3. Reagents and conditions: (a) (COCl)2, DMSO, Et3N, DCM, ꢀ78 °C, 1 h followed by Ph3P@CHCO2Et, 6 h, 82%; (b) DIBAL-H, DCM, 0 °C,
2 h, 79%; (c) D-(ꢀ)-DET, Ti(OiPr)4, TBHP, DCM, ꢀ20 °C, 82%; (d) Ph3P, NaHCO3, CCl4, reflux, 4 h, 79%; (e) LiNH2, ꢀ33 °C or LDA, ꢀ78 °C, 3 h,
82%; (f) Ac2O, Et3N, cat DMAP, DCM, 0 °C, 1 h, 91%.
R
O
OH
a
PMBO
e
+
26
7
27, R = OPMB
28, R = OH
29, R = OTs
30, R = H
b
c
d
OR
OTBDPS
f
i
h
Bu3Sn
33
E:Z (4:1)
31, R = OH
32, R = OTBDPS
g
OTBDPS
Br
6
E:Z (4:1)
Scheme 4. Reagents and conditions: (a) BF3ꢁEt2O, n-BuLi, THF, ꢀ78 °C, 2 h, 76%; (b) DDQ, DCM/H2O (9:1), 3 h, 91%; (c) TsCl, Et3N, cat DMAP,
DCM, 0 °C, 4 h, 88%; (d) LiAlH4, THF, 40 °C, 3 h, 66%; (e) NaNH2, H2N(CH2)3NH2, 80 °C, 4–6 h, 73%; (f) TBDPSCl, imidazole, DCM, 0 °C, 1 h, 96%;
(g) n-Bu3SnH, AIBN, 120 °C, 3 h, 65%; (i) NBS, CH3CN, 0 °C, 2 h, 90%.
O
OR
O
OAc
OTBDPS
a
O
O
OTBDPS
OTBDPS
Br
+
5
6
34, R = OAc
35, R = H
b
OPMB
O
OH
OTBDPS
c
OH
e
R
O
38, R = OH
39, R = OTs
36, R = H
37, R = PMB
f
d
OTBDPS
O
g
BMPO
3
Scheme 5. Reagents and conditions: (a) (Ph3P)4Pd, Et2NH, CuI, toluene, rt, 2 h, 60%; (b) K2CO3, MeOH, rt, 1 h, 81%; (c) LiAlH4, THF, 0 °C, 3 h, 79%;
(d) NaH, PMB–Br, THF, reflux, 12 h, 82%; (e) PTSA, MeOH, rt, 2 h, 74%; (f) TsCl, Et3N, cat DMAP, DCM, 0 °C, 4 h, 75%; (g) K2CO3, MeOH, rt, 2 h,
84%.
Finally tosylate 39 was converted to the corresponding
epoxide in the presence of K2CO3 in MeOH at room tem-
perature to afford the C12–C24 fragment of macrolactin-A
3 (Scheme 5).20

466
J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 463–466
8. Yadav, J. S.; Barma, D. K.; Dinah Dutta Tetrahedron Lett. 1997, 38,
In conclusion, the C1–C11 and C12–C24 fragments of
4479–4482.
macrolactin-A have been synthesized employing Sharpless
asymmetric epoxidation, Wittig, Stille–Gennari and Sono-
gashira reactions as key steps. Efforts to complete the total
synthesis are in progress.
9. Harika, K.; Yoshika, T.; Oikawa, Y.; Yonemistu, O. Tetrahedron
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Acknowledgement
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46, 6567–6570.
M.R.K. thanks CSIR, New Delhi for the award of a
fellowship.
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46, 7033–7046.
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References and notes
1. (a) Gustafon, K.; Roamn, M.; Fenical, W. J. Am. Chem. Soc. 1989,
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986; (c) Nagao, T.; Adachi, K.; Sakai, M.; Nishijima, M.; Sano, H. J.
Antibiot. 2001, 54, 333–339.
3. For total synthesis, see: (a) Smith, A. B., III; Ott, G. R. J. Am. Chem.
Soc. 1996, 118, 13095–13096; (b) Kim, Y.; Singer, R. A.; Carreira, E.
M. Angew. Chem., Int. Ed. 1998, 37, 1261–1263; (c) Marino, J. P.;
McClure, M. S.; Holub, D. P.; Comasseto, J. V.; Tucci, F. C. J. Am.
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19. Nicolaou, K. C.; Laddu Wahetty, T.; Taffer, I. M.; Zipkin, R. E.
Synthesis 1986, 4, 344–347.
25
20. The spectral data of selected compounds. Compound 2: ½aꢂD ꢀ2.5 (c
0.8, CHCl3): 1H NMR (400 MHz, CDCl3): d 0.05 (s, 6H), 0.90 (s, 9H),
2.39–2.45 (m, 2H ), 2.90 (d, J = 1.5 Hz, 1H), 3.72 (s, 3H), 4.21–4.28
(m, 1H), 5.58 (d, J = 11.1 Hz, 1H), 5.64 (dd, J = 5.6, 16.3 Hz, 1H),
6.00 (dt, J = 5.3, 15.2 Hz, 1H), 6.22 (dd, J = 5.2, 15.6 Hz, 1H), 6.54 (t,
J = 11.1 Hz, 1H), 7.40 (dd, J = 11.1, 15.5 Hz, 1H); IR (neat): 2924,
2354, 1686, 1636, 1098 cmꢀ1; FABMS: 320 (M+); Anal. Calcd for
C18H28O3Si: C, 67.46; H, 8.81. Found: C, 67.51; H, 8.87. Compound
4. For partial syntheses, see: (a) Benvegnu, T.; Schio, L.; Le Floc’h, Y.;
Gre´e, R. Synlett 1994, 505–506; (b) Donaldson, W. A.; Bell, P. T.;
Wang, Z.; Bennett, D. W. Tetrahedron Lett. 1994, 35, 5829; (c) Boyce,
R. J.; Pattenden, G. Tetrahedron Lett. 1996, 37, 3501–3504; (d)
25
5: ½aꢂD +57.4, (c 3, CHCl3): 1H NMR (300 MHz, CDCl3): d 1.40–1.62
(m, 10H), 1.91–2.14 (m, 2H), 2.10 (s, 3H), 2.42 (d, J = 2.6 Hz, 1H),
3.52 (dd, J = 4.1, 8.1 Hz, 1H), 4.10 (dd, J = 2.6, 8.1 Hz, 1H), 4.10–
4.20 (m, 1H), 5.34–5.44 (m, 1H); IR (neat): 3283, 2937, 1745,
1106 cmꢀ1; EIMS: m/z 253 (M++H); Anal. Calcd for C14H20O4: C,
66.65; H, 7.99. Found: C, 66.69; H, 7.92. Compound 6: 1H NMR
(300 MHz, CDCl3, E isomer): d 1.04 (s, 9H), 1.06 (d, J = 6.2 Hz, 3H),
1.33–1.55 (m, 4H), 1.91 (q, J = 6.7 Hz, 1H), 2.20 (q, J = 6.7 Hz, 1H),
3.76–3.82 (m, 1H), 5.89 (d, J = 13.9 Hz, 1H), 6.09 (dt, J = 3.0,
15.1 Hz, 1H), 7.35–7.80 (m, 6H), 7.61–7.70 (m, 4H); IR (neat): 2932,
´
Benvegnu, T.; Toupet, L.; Gree, R. Tetrahedron 1996, 52, 11811–
11820; (e) Benvegnu, T.; Gree, R. Tetrahedron 1996, 52, 11821–11826;
(f) Prahlad, V.; Donaldson, W. A. Tetrahedron Lett 1996, 37, 9169–
´
´
´
9172; (g) Gonzalez, A.; Aiguade, J.; Urp, F.; Villarasa, J. Tetrahedron
Lett. 1996, 37, 8949–8952; (h) Tanimori, S.; Morita, Y.; Tsubota, M.;
Nakayama, M. Synth. Commun. 1996, 26, 559–567; (i) Donaldason,
W. A.; Barmann, H.; Prahlad, V.; Tao, C.; Yun, Y. K.; Wang, Z.
Tetrahedron 2000, 56, 2283–2295; (j) Li, S.; Xu, R.; Bai, D.
Tetrahedron Lett. 2000, 41, 3463–3466; (k) Hoffmann, H. M. R.;
Vakalopoulos, A. Org. Lett. 2001, 3, 177–180; (l) Shukun, L.;
Donaldson, W. A. Synthesis 2003, 13, 2064–2068; (m) Fukuda, A.;
Kobayashi, Y.; Kimachi, T.; Takemoto, Y. Tetrahedron 2003, 59,
9305–9313; (n) Li, S.; Xiao, X.; Yan, X.; Xu, R.; Bai, D. Tetrahedron
2005, 61, 11291–11298; (o) Bonin, C.; Chimmiento, L.; Pullez, M.;
Solladie, G.; Colobert, F. J. Org. Chem. 2004, 69, 5015–5022; (p)
Bonin, C.; Chimmiento, L.; Videtta, V.; Colobert, F.; Solladie, G.
Synlett 2006, 2427–2430; (q) Yadav, J. S.; Manoj, K. G.; Pratap, I.
Synthesis 2007, 9, 1343–1348.
;
2858, 1108, 704 cmꢀ1 FABMS: 431 (M+); Anal. Calcd for
C23H31BrOSi: C, 64.02; H, 7.24; Br, 18.52. Found: C, 64.08; H,
7.21; Br, 18.50. Compound 34: 1H NMR (300 MHz, CDCl3): d 1.08
(d, J = 6.2 Hz, 3H), 1.20 (s, 9H), 1.30–1.40 (m, 4H), 1.41–1.65 (m,
10H), 1.88–2.02 (m, 4H), 2.22 (s, 3H), 3.62 (dd, J = 4.4, 12.6 Hz, 1H),
3.80–4.10 (m, 1H), 4.20 (dd, J = 2.9, 12.6 Hz, 1H), 4.30–4.22 (m, 1H),
5.45–5.52 (m, 1H), 6.00 (dt, J = 9.1, 16.2 Hz, 1H), 6.42 (d,
J = 16.2 Hz, 1H,), 7.30–7.80 (m, 6H), 7.60–7.70 (m, 4H); IR (neat):
2935, 2220, 1747, 1590, 1108 cmꢀ1; LCMS: 625 (M++Na); Anal.
Calcd for C37H50O5Si: C, 73.71; H, 8.36. Found: C, 73.74; H, 8.33.
25
Compound 3: ½aꢂD ꢀ46.5 (c 0.3, CHCl3): 1H NMR (300 MHz,
5. For a total synthesis of an analogue of macrolactin-A, see: (a)
Kobayashi, Y.; Fukuda, A.; Kimachi, T.; Ju-ichi, M.; Takemoto, Y.
Tetrahedron Lett. 2004, 45, 677–688; (b) Kobayashi, Y.; Fukuda, A.;
Kimachi, T.; Ju-ichi, M.; Takemoto, Y. Tetrahedron 2005, 61, 2607–
2622.
6. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765–5780.
7. Rama Rao, A. V.; Bhanu, M. N.; Sharma, G. V. M. Tetrahedron Lett.
1993, 34, 707–710.
CDCl3): d 0.98 (s, 9H), 1.20 (d, J = 6.0 Hz, 3H), 1.28–1.58 (m, 4H),
1.79–2.00 (m, 4H), 2.45–2.50 (m, 1H), 2.68–2.77 (m, 1H) 2.98–3.10
(m, 1H) 3.69–3.84 (m, 4H), 3.90–4.06 (m, 1H), 4.25–4.46 (m, 2H), 5.44
(dd, J = 6.3, 15.1 Hz, 1H), 5.58 (dd, J = 6.9, 15.2 Hz, 1H) 5.84–6.15
(m, 2H), 6.80 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H), 7.25–7.40
(m, 6H), 7.54–7.69 (m, 4H); IR (neat): 2927, 1734,1513, 1108, 910,
737, 703 cmꢀ1; LCMS: 607 (M++Na); Anal. Calcd for C37H48O4Si:
C, 75.98; H, 8.27. Found: C, 75.92; H, 8.30.