Studies directed towards the total synthesis of lycoperdinosides: stereoselective construction of the C1-C9 and C10-C21 segments of the molecules

Article abstract of DOI:10.1016/j.tetlet.2007.04.016

The three chiral centres of the C1-C9 moiety of the six-membered lactone glycosides, lycoperdinosides A and B, have been derived from a common starting material containing a single chiral centre. In contrast, the C10-C21 segment of these molecules has bee

Full text of DOI:10.1016/j.tetlet.2007.04.016

Tetrahedron Letters 48 (2007) 4075–4078
Studies directed towards the total synthesis of
lycoperdinosides: stereoselective construction of the C1–C9
and C10–C21 segments of the moleculesI
Tushar Kanti Chakraborty,* Rajib Kumar Goswami and Midde Sreekanth
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 5 March 2007; revised 26 March 2007; accepted 4 April 2007
Available online 11 April 2007
Abstract—The three chiral centres of the C1–C9 moiety of the six-membered lactone glycosides, lycoperdinosides A and B, have
been derived from a common starting material containing a single chiral centre. In contrast, the C10–C21 segment of these molecules
has been synthesized using, as key steps, a highly stereoselective aldol reaction, a Ti(III)-mediated opening of a trisubstituted epoxy
alcohol and an efficient directed hydrostannylation of a suitably substituted internal alkyne.
Ó 2007 Elsevier Ltd. All rights reserved.
Lycoperdinosides A (1) and B (2) were isolated from the
slime mold Enteridium lycoperdon.1 Their structures,
including the absolute configurations of the hydroxyl
and methyl groups, were determined by means of exten-
sive spectroscopic data such as MS, IR, UV, 1D and 2D
NMR spectra along with chemical degradation. The
intricate structures of these molecules make them attrac-
tive targets to synthetic organic chemists. The total syn-
thesis of these molecules would not only provide access
to larger quantities necessary for further biological stud-
ies, but also help to prepare useful analogues. We envis-
aged that the two-halves of the molecules, the C1–C9
unit 3 and the C10–C21 unit 4, could be combined by
a Suzuki coupling reaction2,3 to give the lycoperdinoside
backbone. As part of our studies directed towards the
synthesis of lycoperdinosides, we describe herein the
syntheses of the highly functionalized C1–C9 (3) and
C10–C21 (4) moieties of these molecules in suitably pro-
tected forms.
O
2
O
10
9
OR
O
21
O
O
O
O
1: R =
2: R =
O
OH
O
O
O
O
OH
OTBS
1
OTBS
9
I
+
3
Scheme 1 outlines the details of the synthesis of iodide 3.
Commercially available (S)-3-hydroxy-2-methylprop-
ionic acid methyl ester (5) was transformed into two dif-
ferently protected alcohols 7 and 9, which were then
OBn
I
10
21
TBSO
OTBS
4
linked together through an acetylene. Oxidation of 9
was followed by the conversion of the aldehyde into
an acetylenic group. The anion generated from this acet-
ylenic intermediate was next added to the aldehyde
derived from alcohol 7 to give the desired anti isomer
Keywords: Lycoperdinosides; Aldol reaction; Ti(III); Hydro-
stannylation.
q IICT Communication No. 070305.
*
Corresponding author. Tel.: +91 40 27193154; fax: +91 40 27193275/
27193108; e-mail: chakraborty@iict.res.in
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.016

4076
T. K. Chakraborty et al. / Tetrahedron Letters 48 (2007) 4075–4078
O
MeO
OH
TBDPSO
OH
MeO
OTBS
HO
c
a
HO
OTBS
d
b
TBDPSO
OMe
O
O
9
7
8
6
5
HO
e-h
9
+
TBDPSO
TBDPSO
TBDPSO
j,k
OTBS
OTBS
OTBS
11
10
OH
OTBS
i
OH
10
TBDPSO
OTBS
15
13
12
OTBS
n-p
q,r
l,m
I
I
HO
TBDPSO
14
OH
COOMe
OTBS
OTBS
t
s
3
I
I
17
16
Scheme 1. Synthesis of 3. Reagents and conditions: (a) TBDPSCl, Et3N, DMAP (cat), CH2Cl2, 0 °C to rt, 2 h, 88%; (b) LiBH4, THF, 0 °C to rt, 24 h,
95%; (c) TBSCl, Et3N, DMAP (cat), CH2Cl2, 0 °C to rt, 2 h, 80%; (d) same as in step b, 36 h, 81%; (e) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 °C to
0 °C, 2 h; (f) CBr4, Ph3P, CH2Cl2, 0 °C to rt, 45 min; (g) same as in step e from compound 7; (h) dibromo product of 9 from step f, nBuLi, THF,
ꢀ78 °C to rt, 1 h, cooled to ꢀ78 °C, aldehyde from step g, THF, 30 min, 89% from compound 7; (i) Ni(OAc)2ÆH2O, NaBH4, ethylenediamine, EtOH,
overnight, 88%; (j) TBSOTf, 2,6-lutidine, 0 °C, 10 min, 93%; (k) HF–Py, THF, 0 °C to rt, 6 h, 85%; (l) TsCl, Et3N, DMAP (cat), CH2Cl2, 0 °C to rt,
overnight, 91%; (m) NaI, DMF, 80 °C, 3 h, 74%; (n) same as in step k, overnight, 87%; (o) same as in step j, 0 °C, 10 min, 97%; (p) same as in step k,
64%; (q) same as in step e; (r) CH3O2CCH2P(O)(OCH2CF3)2, NaH, THF, 0 °C, 40 min, then aldehyde from step q, ꢀ78 °C to rt, 1.5 h, 98% after two
steps; (s) DIBAL–H, CH2Cl2, ꢀ78 °C, 10 min, 80%; (t) same as in step j, 5 min, 95%.
10 and syn isomer 11 in almost equal amounts.4 The two
diastereomers were separated easily by standard silica
gel column chromatography and syn isomer 11 could
be recycled to the required diastereomer 10 in two
steps—oxidation with SO3–py and stereoselective
hydride reduction with DIBAL–H to give 10 as the
major isomer in ca. 2:1 ratio.5
thesis of its enantiomer using, in the key steps, a chiral
N-propanoyl oxazolidinethione auxiliary to prepare a
‘non-Evans’ syn aldol adduct9 and a Ti(III)-mediated
opening of a trisubstituted ‘2,3-epoxy alcohol’ to
prepare the ‘2-methyl-1,3-diol’ moiety present in 4.10
Acetonide protection of 18 gave 19, which was then sub-
jected to debenzylation using Li/liq. NH3 to furnish 20.
Tritylation of 20 gave 21, which was desilylated and the
resulting primary alcohol was oxidized to an aldehyde
and reacted with a stabilized ylide to yield a,b-unsatu-
rated ester 22. Reduction of 22 gave 23, which was pro-
tected as the corresponding Bn–ether 24. Acid treatment
of 24 removed the trityl as well as the acetonide protec-
tion. The resulting triol 25 was persilylated and then
subjected to selective deprotection of the primary silyl
ether to give 26. Oxidation of 26 was followed by reac-
tion with the stabilized ylide (carbethoxyethylidene)tri-
phenylphosphorane to furnish a,b-unsaturated ester
27. Reduction of the ester group of 27 gave alcohol
28, which was converted to acetylene 29.
Controlled hydrogenation of the acetylenic moiety of 10
was achieved using P2-Ni6 to give Z-allylic alcohol 12.
Silylation of 12 was followed by the selective deprotec-
tion of the primary-OTBS to give 13. Tosylation of 13
gave the primary tosylate, which was transformed into
iodide 14. Our failure to selectively desilylate the pri-
mary O-silyl group in 14 required us to deprotect both
the silyl groups, reprotect them as TBS–ethers and then
carry out the desired selective desilylation to give 15.
Oxidation of 15 was followed by selective Z-olefination
using the ketophosphonate, (CF3CH2O)2P(O)CH2-
CO2Me,7 to give 16 as the major product in ca. 10:1
ratio. The minor isomer could be removed chromato-
graphically after the reduction step. Reduction of 16
with DIBAL–H was followed by silylation to furnish
the target intermediate 3.8
Methylation of the terminal acetylenic moiety of 29 and
conversion of the resulting internal alkyne to target 4
using a hydrozirconation–iodination sequence11 failed
to provide the desired product. Even Pd(0)-catalyzed
hydrostannylation12 did not yield the expected result.
Finally, we adopted the protocol developed by Marshall
and Bourbeau to synthesize the polypropionate subunit
Synthesis of the C10–C21 segment 4 is described in
Schemes 2 and 3. The starting material 18 was prepared
following the method reported earlier by us5 for the syn-

T. K. Chakraborty et al. / Tetrahedron Letters 48 (2007) 4075–4078
4077
a
b
OTBDPS
OTBDPS
BnO
OTBDPS
BnO
TrO
HO
HO
O
O
OH OH
O
O
18
19
TrO
20
d-f
c
g
OTBDPS
TrO
COOEt
O
O
O
O
21
22
OH
i
OBn
TrO
h
OBn
HO
O
O
O
O
25
OH OH
23
24
j,k
n
l,m
OBn
HO
OBn
EtOOC
OTBS
OTBS
OBn
26
27
TBSO
OTBS
TBSO
o-q
OBn
OTBS
TBSO
TBSO
28
29
Scheme 2. Reagents and conditions: (a) 2,2-DMP, CSA, CH2Cl2, 0 °C to rt, overnight, 98%; (b) Li, liq. NH3, THF, ꢀ33 °C, 10 min, 78%; (c) TrCl,
Et3N, DMAP (cat), CH2Cl2, 0 °C to rt, overnight, 70%; (d) TBAF, THF, 0 °C to rt, overnight, 92%; (e) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 °C to
0 °C, 2 h; (f) Ph3P@CHCO2Et, CH2Cl2, rt, overnight, 89% in two steps; (g) LiBH4, THF, 0 °C to rt, 16 h, 86%; (h) BnBr, NaHMDS, THF:DMF
(2:1), 0 °C to rt, overnight, 96%; (i) 20% TFA in tBuOH, rt, 2 h, 65%; (j) TBSOTf, 2,6-lutidine, 0 °C, 10 min, quantitative; (k) HF–Py, THF, 0 °C to
rt, 5 h, 75%; (l) SO3-Py, DMSO, CH2Cl2, 0 °C to rt, 30 min; (m) Ph3P@C(Me)CO2Et, CH2Cl2, rt, overnight, 80% in two steps; (n) DIBAL–H,
CH2Cl2, ꢀ78 °C, 15 min, quantitative; (o) same as in step l; (p) CBr4, Ph3P, CH2Cl2, 0 °C, 30 min; (q) EtMgBr, THF, ꢀ78 °C to 0 °C, 1 h, 90% in
three steps.
OBn
OBn
c
b
a
AcO
29
HO
OTBS
OTBS
30
TBSO
TBSO
31
AcO
AcO
I
e
d
OBn
OBn
Bu3Sn
OTBS
OTBS
33
TBSO
TBSO
32
terminal : internal stannane (3:1)
HO
I
Br
I
h
OBn
f,g
OBn
4
OTBS
OTBS
34
35
TBSO
TBSO
Scheme 3. Synthesis of 4. Reagents and conditions: (a) nBuLi, (HCHO)n,THF, ꢀ78 °C to rt, overnight, 72%; (b) Ac2O, Et3N, DMAP (cat), CH2Cl2,
0 °C, 5 min, quantitative; (c) Bu3SnH, Pd(Ph3P)2Cl2, THF, rt, 30 min, 71%; (d) I2, CH2Cl2, ꢀ78 °C to 0 °C, 30 min, 95%; (e) 3 N NaOH,
THF:MeOH (5:1), 0 °C, 10 min, 86%; (f) MsCl, Et3N, CH2Cl2, 0 °C, 10 min; (g) LiBr, acetone, rt, 2 h, 68% in two steps; (h) LiEt3BH, THF, 0 °C,
10 min, 85%.
of callystatin A.13 This enabled us to achieve our target
and the results are outlined in Scheme 3. Hydroxy-
methylation of 29 gave propargylic alcohol 30, which
was acylated to give acetate 31. As noted previously,13,14
hydrostannylation of 31 was very successful and pro-
ceeded with good selectivity due to the influence of the
acylated hydroxymethyl group to give the terminal-stan-
nylated product 32 as the major product in a 3:1 ratio.
The minor isomer could be separated easily by column
chromatography after two further steps. Iodination of
32 gave vinyl iodide 33, which required four more
steps—deacylation, mesylation, bromination and finally
reduction with super hydride—to furnish the target
molecule 4.15

4078
T. K. Chakraborty et al. / Tetrahedron Letters 48 (2007) 4075–4078
(neat): mmax 2955, 2926, 2855, 1632, 1463, 1253, 1082 cmꢀ1
;
Unfortunately, our attempts to couple the two-halves, 3
and 4 either by exchanging the primary iodo group of 3
with zinc using tBuLi and anhydrous ZnCl2 followed by
coupling with 4 using Pd(Ph3P)4 in THF,16 or reacting
1H NMR (300 MHz, CDCl3): (atom numbering from
right): d 5.57–5.09 (m, 4H, C3–H, C4–H, C7–H, C8–H),
4.26–4.13 (m, 3H, C5–H, C9–H2), 3.13 (dd, J = 9.8,
5.3 Hz, 1H, C1–Ha), 3.02 (dd, J = 9.8, 7.6 Hz, 1H, C1–
Hb), 2.60 (m, 1H, C6–H), 2.44 (m, 1H, C2–H), 1.08 (d,
J = 6.8 Hz, 3H, C–CH3), 0.96 (d, J = 6.8 Hz, 3H, C–
t
the boronate ester derived from 3, using BuLi and 9-
methoxy-9-BBN, with 4 using Pd(dppf)Cl2, aqueous
K3PO4 in DMF2,17 were unsuccessful leaving the total
syntheses of the lycoperdinosides unfinished. Further
work in this direction is in progress.
t
CH3), 0.90–0.88 (two s, 18H, two Bu), 0.06–0.04 (two s,
12H, four Si–CH3); 13C NMR (50 MHz, CDCl3): d 132.7,
132.5, 132.3, 129.9, 72.2, 59.7, 34.4, 31.9, 25.9, 25.8,
21.6, 18.3, 18.1, 16.8, 13.9, ꢀ4.7, ꢀ5.1; HRMS (LSIMS):
Calcd for C23H47O2NaSi2I [M+Na]+: 561.2057. Found:
561.2046.
Acknowledgements
9. (a) Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am.
Chem. Soc. 1997, 119, 7883–7884; For some earlier leading
references on oxazolidinethione based aldol reactions
giving ‘non-Evans’ syn products see the following review
articles (b) Fujita, E.; Nagao, Y. Adv. Heterocycl. Chem.
1989, 45, 1–36; (c) Mukaiyama, T.; Kobayashi, S. Org.
React. 1994, 46, 1–103.
The authors wish to thank DST, New Delhi, for a Ram-
anna Fellowship (SR/S1/RFOC-06/2006; T.K.C.) and
CSIR, New Delhi, for research fellowships (R.K.G.
and M.S.).
References and notes
10. (a) Chakraborty, T. K.; Dutta, S. J. Chem. Soc., Perkin
Trans. 1 1997, 1257–1259; (b) Chakraborty, T. K.; Das, S.
Tetrahedron Lett. 2002, 43, 2313–2315.
ˇ
´
´
ˇ
1. Rezanka, T.; Dvorˇakova, R.; Hanus, L. O.; Dembitsky, V.
11. (a) Hart, D. W.; Blackburn, T. F.; Schwartz, J. J. Am.
Chem. Soc. 1975, 97, 679–680; (b) Negishi, E.-I. In
Organometallics in Synthesis, 2nd ed.; Schlosser, M., Ed.;
Wiley and Sons, Ltd: Chichester, UK, 2002; p 934; (c)
Panek, J. S.; Hu, T. J. Org. Chem. 1997, 62, 4912–
4913.
M. Eur. J. Org. Chem. 2004, 995–1001.
2. (a) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron
Lett. 1979, 20, 3437–3440; (b) Miyaura, N.; Suzuki, A. J.
Chem. Soc., Chem. Commun. 1979, 866–867; For reviews
see (c) Suzuki, A. Acc. Chem. Res. 1982, 15, 178–184; (d)
Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483;
(e) Suzuki, A. Chem. Commun. 2005, 4759–4763; (f)
Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem.,
Int. Ed. 2005, 44, 4442–4489.
12. (a) Zhang, H.-X.; Guibe, F.; Balavoine, G. J. Org. Chem.
´ ´
1990, 55, 1857–1867; (b) Benechie, M.; Skrydstrup, T.;
Khuong-Huu, F. Tetrahedron Lett. 1991, 32, 7535–7538.
13. Marshall, J. A.; Bourbeau, M. P. Org. Lett. 2002, 4, 3931–
3934.
3. Marshall, J. A.; Bourbeau, M. P. J. Org. Chem. 2002, 67,
2751–2754.
14. (a) Miyake, H.; Yamakura, K. Chem. Lett. 1989, 981–984;
(b) Rice, M. B.; Whitehead, S. L.; Horvath, C. M.;
Muchnij, J. A.; Maleczka, R. E. Synthesis 2001, 1495–
1504.
4. To prove the stereochemistry of the adduct, compound 10
was transformed into acetonide 36. The 3J value of the
propargylic proton, „–CH(O–), in 36 was 10.4 Hz,
confirming a diaxial relationship with its vicinal proton
and proving the assigned stereochemistry
15. Selected physical data for 4: Rf = 0.63 (silica gel, 10%
EtOAc in petroleum ether); ½aꢁ2D8 +6.51 (c 0.22, CHCl3); IR
(neat): mmax 2924, 2853, 1461, 1253 cmꢀ1 1H NMR
;
1. TBAF, THF, 0 oC to rt, 4 h
O
(200 MHz, CDCl3): (atom numbering from left): d 7.32–
7.28 (m, 5H, ArH), 6.58 (s, 1H, C3–H), 5.31 (t, J = 6.5 Hz,
1H, C5–H), 4.48 (s, 2H, PhCH2O–), 3.86 (m, 1H, C7–H),
3.53 (dd, J = 7.3, 1.4 Hz, 1H, C9–H), 3.43 (t, J = 6.0 Hz,
2H, C13–H2), 2.53 (d, J = 1.4 Hz, 3H, C2–CH3), 2.25 (m,
2H, C6–H2), 1.70 (s, 3H, C4–CH3), 1.66–1.49 (m, 6H, C8–
O
10
2. 2,2-DMP, CSA, CH2Cl2, 0 oC
to rt, 0.5 h (74% in two steps)
36
OH
t
5. Chakraborty, T. K.; Reddy, V. R.; Reddy, T. J. Tetra-
hedron 2003, 59, 8613–8622.
6. Brown, C. A.; Ahuja, V. K. J. Org. Chem. 1973, 38, 2226–
2230.
H, C10–H, C11–H2, C12–H2), 0.93–0.79 (m, 24H, two Bu,
C8–CH3, C10–CH3), 0.07–0.03 (three s, 12H, four Si–CH3);
HRMS (LSIMS): Calcd for C35H63O3NaSi2I [M+Na]+:
737.3258. Found: 737.3260.
7. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405–
4408.
16. Smith, A. B., III; Qiu, Y.; Jones, D. R.; Kobayashi, K.
J. Am. Chem. Soc. 1995, 117, 12011–12012.
17. Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63,
7885–7892.
8. Selected physical data for 3: Rf = 0.60 (silica gel, 4%
EtOAc in petroleum ether); ½aꢁ2D8 +14.8 (c 0.71, CHCl3); IR