Stereoselective Formal Synthesis of (-)-Salicylihalamides A and B Via Prins Cyclisation

Article abstract of DOI:10.2174/157017810791824856

A stereoselective and convergent formal approach to Salicylihalamide A and B is achieved through our recently developed strategy for the construction of polyketide precursors via Prins cyclisation. The approach mainly relies upon reductive opening of 1-iodomethyl cyclic ethers, Mitsunobu inversion and ring closing metathesis along with Prins cyclisation.

Full text of DOI:10.2174/157017810791824856

Letters in Organic Chemistry, 2010, 7, 457-460
457
Stereoselective Formal Synthesis of (-)-Salicylihalamides A and B Via Prins
Cyclisation
J.S. Yadav*, N. Venkateswar Rao, P. Purushothama Rao, M. Sridhar Reddy and
A.R. Prasad
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad-500 007, India
Received June 17, 2009: Revised March 10, 2010: Accepted March 25, 2010
Abstract: A stereoselective and convergent formal approach to Salicylihalamide A and B is achieved through our recently
developed strategy for the construction of polyketide precursors via Prins cyclisation. The approach mainly relies upon
reductive opening of 1-iodomethyl cyclic ethers, Mitsunobu inversion and ring closing metathesis along with Prins
cyclisation.
Keywords: Natural products, cytotoxicity, prins cyclisation, reductive cleavage, mitsunobu inversion and ring closing
metathesis.
Salicylihalamides A and B (1 and 2; Fig. 1) comprise a
novel class of secondary metabolites isolated by Boyd and
co-workers [1] in 1997 from the marine sponge Haliclona.
Salicylihalamide A (1) displays potent cytotoxicity in the
NCI 60-cell line Human tumor assay, with a mean GI50
value of 15 nM through a distinct mechanism of action [1,2].
Few pharmacological studies however do indicate that
Salicylihalamide A selectively inhibits mammalian vacuolar-
type (H+)-ATPase (V-ATPase) [3]. Hence, these molecules
engendered considerable interest with in the synthetic
community [4].
In our retrosynthetic analysis (Fig. 1), it is evident that
the core part of the Salicylihalamides could be easily
obtained from aliphatic part 3 and aromatic fragment 4 via
an esterification and ring closing metathesis. The aliphatic
part 3 is envisaged to be constructed from homoallylic
alcohol 5 which in turn could be drawn, via pyranyl
methanol 6, through Prins cyclisation between 7 and 8
following our recently developed methodology [6].
Synthesis of aliphatic fragment 3 is depicted in Scheme
1. Prins cyclisation between known homoallylic alcohol 7
[6] and aldehyde 8 [6] in the presence of TFA [5] resulted in
OTBS
OH
OTBS
HN
17
OMOM
O
HO
OH
O
O
6
OBn
HO
OBn
OH
5
1
O
3
OH
13
Prins
Cyclisation
OMe
O
10
OH
salicylihalamide A (1) : 17 E
salicylihalamide B (2) : 17 Z
HO
7
OH
4
+
OBn
O
8
Fig. (1). Retrosynthetic analysis of salicylihalamides A and B.
Inspired by the biological properties and because of
limited availability of the natural product and, as a part of
our successful efforts towards the total synthesis of many
ketide natural products via Prins cyclisation [5,6], we
investigated a formal synthesis of Salicylihalamide A and B.
trifluoroacetate of 6 which on treatment with K2CO3 in
MeOH gave tetrahydropyran diol 6 in 55 % yield. Tosylation
of primary hydroxyl group using TEA and protection of
secondary hydroxyl group as TBS ether using TBDMSCl
and imidazole produced 9 in 88 % over all yield.
Substitution of tosylate group in 9 with iodide in presence of
NaI in acetone followed by reductive elimination using Zn in
EtOH produced alcohol 5 in 90% over two steps. Protection
of the resulting alcohol as its MOM ether in presence of
*Address correspondence to this author at the Division of Organic
Chemistry, Indian Institute of Chemical Technology, Hyderabad-500 007,
India; Fax: 91-40-27160512; E-mail: yadavpub@iict.res.in
1570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

458 Letters in Organic Chemistry, 2010, Vol. 7, No. 6
Yadav et al.
OTBS
OTBS OMOM
f
a
b, c
d, e
5
OBn
7 + 8
6
TsO
O
OBn
10
9
OTBS OMOM
OTBS OMOM
g, h
k, l
i, j
HO
OBn
TBSO
OH
12
11
OH
OMOM
OTBS OMOM
o
m, n
3
HO
TBSO
13
14
Scheme 1. Reagents and conditions: (a) TFA, CH2Cl2, 0 oC-rt, 3h then K2CO3, MeOH, rt, 30 min, 55%; (b) TsCl, TEA, CH2Cl2, 0 oC-rt, 3 h,
o
85%; (c) TBDMSCl, imidazole, DMAP, CH2Cl2, 0 C-rt, 6 h, 92%; (d) NaI, acetone, reflux, 24h, 90%; (e) Zn, EtOH, reflux, 2h, 92%; (f)
o
MOMCl, DIPEA, DMAP, CH2Cl2, 0oC-rt, 6h, 85%; (g) O3, Ph3P, CH2Cl2, -78 C; (h) NaBH4, MeOH, 0oC, 30 min (80% yield over two
o
o
steps); (i) TBDMSCl, imidazole, CH2Cl2, 0 C-rt, 3 h, 90%; (j) Na, NH3, THF, 20 min, 85 %; (k) TsCl, TEA, CH2Cl2, 0 C-rt, 3h, 91%; (l)
HCꢀCLi, DMSO, rt, 3h, 68 %; (m) cat. Pd-BaSO4, H2, rt, 6 h, 92 %; (n) TBAF, THF, rt, 8 h, 85%; (o) TBDMSCl, imidazole, THF, 0 oC-rt ,
83 %.
MOMCl and DIPEA gave 10. Ozonolytic cleavage of olefin
group in 10 followed by reduction of resulting aldehyde with
NaBH4 has yielded alcohol 11 with 80% yield over two
steps. Protection of free hydroxyl as TBS ether and
deprotection of benzyl group (using Na in NH3) produced the
alcohol 12. The alcohol 12 is transformed to corresponding
tosylate and then exposed to lithium acetylide to get
homologated alkyne 13 [7]. Controlled reduction of alkyne
group in 13 using Lindlars’ catalyst produced corresponding
olefin which on deprotection of TBDMS groups with TBAF
produced alcohol 14. Selective protection of primary
hydroxyl group in 14 as TBS ether furnished key aliphatic
fragment 3.
4 in 86 % yield in 4 steps. The stage was now set for the
coupling between 3 and 4.
Esterification of 3 with 4 using DCC/DMAP or in
Yamaguchi conditions [8] (2,4,6 trichlorobenzoyl chloride,
TEA, THF, 4-DMAP, PhMe) met with failure in all possible
alterations in reaction conditions. Then, we opted for the
Mitsunobu conditions [9]. Prior to that, the hydroxyl group
in 3 was inverted in standard Mitsunobu conditions so that
the center will remain as such after the coupling of 17 with
4. Thus, the esterification of 17 with 4 in Mitsunobu
conditions smoothly resulted in 18. Ring closing metathesis
[10] of 18 using Grubbs’ second generation catalyst followed
by deprotection of TBS ether led to formal synthesis of
Salycilihalamide A and B. Synthetic compound has showed
spectral and analytical data (1H NMR, 13C NMR, IR, Rf and
[ꢀ]D) identical to the previously synthesized sample [4e].
Synthesis of aromatic fragment 4 is described in Scheme
2. Esterification of benzoic acid 15 using DBU and MeI gave
a hydroxyl ester which on treatment with Tf2O produced
triflate 16. Subjection of triflate 16 to allylation in Stille
coupling conditions (allyl tributyl tin and lithium chloride)
followed by hydrolysis of ester group using LiOH furnished
In summary, we have described a convergent formal
approach to Salicylihalamides A and B using our recently
OTBS
OMe
O
OMe
O
OMe
O
OMe
O
OH
OMe
OMOM
a, b
OH
c, d
O
e, 3
OH
OTf
15
16
4
18
OH
OMe
O
OH
OMOM
OMOM
ref 4e
g
O
h, i
f
1 & 2
18
3
TBSO
17
19
o
Scheme 2. Reagents and conditions: (a) DBU, MeI, THF, 0 C-rt, 24 h, 82%; (b) Tf2O, Py, 0oC-rt, 20 h, 89%; (c) LiCl, allyl tributyl tin
o
o
hydride, DMF, 0 C-rt, 4 h; 82% (d) LiOH.H2O, MeOH, 65 C, 72 h, 95%; (e) i) 2,4,6-trichlorobenzoyl chloride, TEA, THF, 4-DMAP,
PhMe, or ii) DCC, DMAP, CH2Cl2, rt; (f) DEAD, p-nitro benzoic acid, Ph3P, THF, 0 oC-rt, 30 min then K2CO3, MeOH, rt, 30 min, 85%; (g)
DEAD, 4, Ph3P, Benzene, rt, 2hrs, 90%; (h) Grubbs II catalyst, CH2Cl2, rt, 85% (9:1); (i) TBAF, THF, 0 oC - rt, 92 %.

Stereoselective Formal Synthesis of (-)-Salicylihalamides
Letters in Organic Chemistry, 2010, Vol. 7, No. 6
459
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ACKNOWLEDGEMENTS
NVR, PPR and MSR thank CSIR, New Delhi for the
award of fellowship and also thank DST for the financial
assistance under JC Bose Fellowship scheme.
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[11]
Spectral Data of Selected Compounds: colourless liquid; [ꢀ]25D -2.2
(c = 1.5, CHCl3) Rf = 0.2 (EtOAc: Hexane, 60:40); IR (KBr): ꢁmax
3384, 2921, 2854, 1059 cm-1; 1H NMR (300 MHz, CDCl3): ꢂ 7.35-
7.23 (m, 5H), 4.52-4.43 (m, 2H,), 3.91-3.71 (m, 2H), 3.60-3.30 (m,
5H), 2.02-1.71 (m, 3H), 1.5-1.46 (m, 1H), 1.22-1.09 (m, 1H), 0.95
(d, 3H, J = 6.8 Hz); 13C NMR (75 MHz, CDCl3): ꢂ 138.4, 128.3,
127.5, 76.5, 75.8, 73.0, 72.0, 68.0, 65.7, 37.3, 36.7, 34.1, 12.2,
HRMS (ESI): m/z calcd for C16H24O4Na [M+Na]+ 303.1572, found
303.1587. Spectral Data of Selected Compounds: colourless liquid;
[ꢀ]25D +18.5 (c = 1.5, CHCl3); Rf = 0.5 (EtOAc: Hexane, 20:80); IR
(KBr): ꢁmax 3508, 2930, 2857, 1068 cm-1; 1H NMR (300 MHz,
CDCl3): ꢂ 7.32-7.21 (m, 5H), 5.80-5.66 (m, 1H,), 5.07-4.98 (m,

460 Letters in Organic Chemistry, 2010, Vol. 7, No. 6
Yadav et al.
2H), 4.53-4.45 (m, 2H), 4.09-3.92 (m, 1H), 3.78-3.69 (m, 1H),
3.53-3.41 (m, 2H), 2.32-2.25 (m, 2H, J = 6.7, 6.0 Hz), 1.86-1.70
(m, 1H), 1.62-1.35 (m, 2H), 0.93-0.87 (m, 12H), 0.09 (s, 3H), 0.08
(s, 3H). 13C NMR (75 MHz, CDCl3): ꢀ 138.2, 134.7, 128.2, 127.4,
117.1, 73.8, 73.2, 71.1, 70.0, 41.7, 39.7, 39.1, 25.8, 18.0, 13.7, -4.4,
-4.8. HRMS (ESI): m/z calcd for C22H38O3NaSi [M+Na]+ 401.2487,
found 401.2484. Spectral Data of Selected Compounds: clear oil.
[ꢀ]25 -31.3 (c 0.5, CHCl3), [lit.4e [ꢀ]25 -34.5 (c 1.0, CHCl3)]. IR
6.8Hz ,1H), 4.45 (d, J = 6.8Hz , 1H ), 3.91 –3.82 (m, 1H), 3.79(s,
3H), 3.72 (q, J = 10.3Hz, 2H), 3.63 (dd, J = 11.9 Hz, 2.6Hz, 1H),
3.29 (s, 3H), 3.18 (dd, J = 11.9 Hz, 2.6Hz ,1H), 2.91 (br s, 1H, OH),
2.03–1.52 (m, 7H), 0.96 (d, J = 6.8Hz, 3H) 13C NMR (CDCl3, 75
MHz): ꢁ = 167.7, 157.2, 139.7, 133.2, 130.6, 128.7, 124.6, 123.3,
109.8, 95.8, 78.7, 73.7, 58.7, 55.9, 55.3, 38.3, 38.2, 37.4, 34.7, 14.5.
HRMS (ESI): m/z [M+Na]+ calcd for C21H30NaO6: 401.1940;
found : 401.1943.
D
D
(neat): 3470, 2927, 1721, 1583, 1466, 1274 cm-1. 1H NMR (CDCl3,
500 MHz): ꢁ = 7.29 –7.23 (m, 1H), 6.81(t, J = 8.6Hz, 2H), 5.49–
5.40(m, 1H), 5.35–5.27 (m, 1H), 5.20-5.12 (m, 1H), 4.56 (d, J =