Olefin metathesis-iodoetherification-dehydroiodination strategy for spiroketal subunits of polyether antibiotics

Article abstract of DOI:10.1021/jo9014722

(Chemical Equation Presented) The convergent synthesis of two pentacyclic analogues of the polyether monensin A is described. Although different with respect to the configuration of the alcohol at the 3 position of the six-membered ring of the spiroketal

Full text of DOI:10.1021/jo9014722

pubs.acs.org/joc
Olefin Metathesis-Iodoetherification-Dehydroiodination Strategy for
Spiroketal Subunits of Polyether Antibiotics
†
Kurissery A. Tony, Darrin Dabideen, Jialiang Li, Maria Dolores Dıaz-Hernandez,
†
†
‡
ꢀ
‡
Jesus Jimenez-Barbero, and David R. Mootoo*
,†
ꢀ
ꢀ
†Department of Chemistry, Hunter College/CUNY, 695 Park Avenue, New York, New York 10021, and
‡Chemical and Physical Biology, CIB-CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain
dmootoo@hunter.cuny.edu
Received July 15, 2009
The convergent synthesis of two pentacyclic analogues of the polyether monensin A is described.
Although different with respect to the configuration of the alcohol at the 3 position of the six-
membered ring of the spiroketal subunit, the configuration at the acetal center in both structures is
unchanged and is consistent with the anomeric effect. The key synthetic steps are the coupling of two
complex segments via an olefin metathesis, and the subsequent conversion of a dihydroxyalkene to
the spiroketal through an iodoetherification-dehydroiodination sequence. The compatibility of
these transformations with a variety of functional groups makes the overall strategy appropriate for
highly substituted frameworks.
Introduction
for the polyether antibiotics, we targeted the monensin
analogue 2. Mimetics like 2 that have unnatural substitution
patterns are of interest in that such modifications may alter
the natural configuration at the spiroketal center, leading to
pronounced effects on overall molecular shape and conse-
quently cation binding.2 In this context, the spiroketal con-
figuration in monensin is believed to be thermodynami-
cally favored by the anomeric effect in the six-membered
ring and hydrogen bonding between the ring alcohol and the
The polyether antibiotics, of which monensin 1 is a well-
known example, are known for a variety of different bio-
logical effects (Figure 1).1 Their ability to mediate ion trans-
port across biological membranes, which in part has been
related to their mode of action, has inspired structure
activity and computational investigations.2 As part of a
program on complex spiroketals, we have been developing
an unusual olefination-iodoetherification-spiroketaliza-
tion strategy.3-5 To test the feasibility of this methodology
(5) Recent syntheses of complex spiroketals: (a) Hao, J.; Forsyth, C. J.
Tetrahedron Lett. 2002, 43, 1–2. (b) Crimmins, M. T.; Katz, J. D.; Washburn,
D. G.; Allwein, S. P.; McAtee, L. F. J. Am. Chem. Soc. 2002, 124, 5661–5663.
(c) Holson, E. B.; Roush, W. R. Org. Lett. 2002, 4, 3719–3723. (d) Tsang,
K. I.; Brimble, M. A.; Bremner, J. B. Org. Lett. 2003, 5, 4425–4427. (e) Wang,
L.; Floreancig, P. E. Org. Lett. 2004, 6, 569–572. (f) Liu, J.; Hsung, R. P. Org.
Lett. 2005, 7, 2273–2276. (g) Statsuk, A. V.; Liu, D.; Kozmin, S. J. Am. Chem.
Soc. 2004, 126, 9546–9547. (h) Takaoka, L. R.; Buskmelter, A. J.; LaCruz,
T. E.; Rychnovsky, S. D. J. Am. Chem. Soc. 2005, 127, 528–529. (i) Potuzaz,
J. S.; Moilanen, S. B.; Tan, D. S. J. Am. Chem. Soc. 2005, 127, 13796–13797.
(j) Nicolaou, K. C.; Frederick, M. O.; Petrovic, G.; Cole, K. P.; Loizidou,
E. Z. Angew. Chem., Int. Ed. 2006, 45, 2609–2615. (k) Zhou, X.-T.; Carter,
R. G. Angew. Chem., Int. Ed. 2006, 45, 1787–1790. (l) Li, Y.; Zhou, F.;
Forsyth, C. J. Angew. Chem., Int. Ed. 2007, 46, 279–282. (m) Evans, D. A.;
Dunn, T. B.; Kvrnø, L.; Beauchemin, A.; Raymer, B.; Olhava, E. J.; Mulder,
J. A.; Juhl, M.; Kagechika, K.; Favor, D. A. Angew. Chem., Int. Ed. 2007, 46,
4698–4703.
(1) Polyether Antibiotics: Naturally Occurring Acid Ionophores; Westley,
J. W., Ed.; Marcel Dekker: New York, 1982; Vols. 1 and 2.
ꢁ
(2) (a) Peyrat, J.-F.; Figadere, B.; Cave, A. Tetrahedron Lett. 1995, 36,
7653–7656. (b) Wang, X.; Erickson, S. D.; Iimori, T.; Still, W. C. J. Am.
Chem. Soc. 1992, 114, 4128–4137. (c) Li, G.; Still, W. C. Tetrahedron Lett.
1993, 34, 919–922.
(3) (a) Li, X.; Li, J.; Mootoo, D. R. Org. Lett. 2007, 9, 4303–4306. (b) Tony,
K. A.; Li, X.; Dabideen, D.; Li, J.; Mootoo, D. R. Org. Biomol. Chem. 2008, 6,
1165–1169. (c) Li, J.; Li, X.; Mootoo, D. R. Nat. Prod. Commun. 2008, 3, 1771–
1780.
(4) Reviews on spiroketals: (a) Favre, S.; Vogel, P.; Gerber-Lemaire, S.
Molecules 2008, 13, 2570. (b) Raju, B. R.; Saika, A. K. Molecules 2008, 13,
1942–2038. (c) Aho, J. E.; Pihko, P. M.; Rissa, T. K. Chem. Rev. 2005, 105,
4406–4440. (d) Mead, K. T.; Brewer, B. N. Curr. Org. Chem. 2003, 7, 227–
225. (e) Brimble, M. A.; Furkert, D. P. Curr. Org. Chem. 2003, 7, 1461–1484.
7774 J. Org. Chem. 2009, 74, 7774–7780
Published on Web 09/24/2009
DOI: 10.1021/jo9014722
r
2009 American Chemical Society

Tony et al.
JOCArticle
SCHEME 2. Synthesis of Alkene 6
FIGURE 1. Simplified monensin mimetics.
SCHEME 1. Retrosynthetic Analysis
Protecting group removal in 3 and spiroketal equilibration
provides 2 (Scheme 1).
Results and Discussion
The tetracyclic homoallylic alcohol 7 was available from an
earlier investigation.11 The synthesis of the less complex alkene
partner 6 started from commercially available 5-benzyloxypen-
tanal 812 (Scheme 2). Thus Keck allylation on 8 using (R)-1,
10-bi-2-naphthol (BINOL) provided the derived homoallylic
alcohol, which showed an enantiomeric excess of greater than
95% by analysis of the R-methoxy-R-trifluoromethylphenyl-
acetic acid (MTPA) ester derivatives.13,14 Alcohol protection
as the PMB ether followed by oxidative cleavage of the
alkene provided aldehyde 9. Unfortunately, the synthesis of
the required syn diol derivative 6, through the reaction of a
variety of achiral and chiral allylating agents with 9, was not
highly selective.15 The most practical route to 6 was to separate
the 1:1 mixture of products from the reaction of 9 with
allylmagnesium bromide, as the MOM derivatives 10 and 11,
and remove the PMB ether in the syn diol precursor 10. The
stereochemistry of 10 and 11 was assigned through analysis of
the corresponding acetonides (Supporting Information).16
Although a cross metathesis (CM) on 6 and 7 provides a
direct route to 5, we opted for a ring-closing metathesis
(RCM) strategy on a mixed phthalate derivative 12,17 be-
cause the CM of such type I metathesis partners is expected
to lead to substantial homodimer formation (Scheme 3).18
Thus, 12 was obtained, from the DCC-mediated coupling of
anomeric oxygen.4,6-9 On this basis, we speculated that the
simplified analogue 2, in which the relative configuration at
C-19 and C-21 of the six-membered ring is the same as in 1,
would favor the analogous spiroketal configuration. Retro-
synthetically, we envisaged a convergent strategy in which
alkene precursors 6 and 7 are coupled via a metathesis
protocol to give the dihydroxyalkene 5. Regioselective io-
doetherification of 5 gives iodo-tetrahydropyran 4, which
when exposed to silver triflate leads to spiroketal 3. Thus, the
alkene in 5 is the functional equivalent of an alkyne.10
(11) Dabideen, D.; Mootoo, D. R. Tetrahedron Lett. 2003, 44, 8365–
8368.
(12) Nagaoka, H.; Miyakoshi, T.; Kasuga, J.; Yamada, Y. Tetrahedron
Lett. 1985, 26, 5055–5056.
(13) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993, 115,
8467–8468.
(14) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512–519.
Curran, D. P.; Sui, B. J. Am. Chem. Soc. 2009, 131, 5411–5413.
(15) Danishefsky, S. J.; DeNinno, M. P.; Phillips, G. B.; Zelle, R. E.;
Lartey, P. A. Tetrahedron 1986, 42, 2809–2819. Roush, W. R.; Hoong, L. K.;
Palmer, M. A.; Park, J. C. J. Org. Chem. 1990, 55, 4109–4117. Racherla,
U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401–404.
(16) Rychnovsky, S. D.; Rogers, B. N.; Richardson, T. I. Acc. Chem. Res.
1998, 31, 9–17.
(6) Fukuyama, T.; Akasaka, K.; Karanewsky, D. S.; Wang, C.-L.;
Schmid, G.; Kishi, Y. J. Am. Chem. Soc. 1979, 101, 262–263.
(7) Cai, D.; Still, W. C. J. Org. Chem. 1988, 53, 4643–4644.
(8) (a) Ireland, R. E.; Armstrong, J. D. III; Lebreton, J.; Meissner, R. S.;
Rizzacasa, M. A. J. Am. Chem. Soc. 1993, 115, 7152–7166. (b) Ireland, R. E.;
Meissner, R. S.; Rizzacasa, M. A. J. Am. Chem. Soc. 1993, 115, 7166–7172.
(9) Lutz, W. K.; Winkler, F. K.; Dunitz, J. D. Helv. Chim. Acta 1971, 54,
1103–1108.
(17) Fan, G.-T.; Hus, T.-S.; Lin, C.-C.; Lin, C.-C. Tetrahedron Lett. 2000,
41, 6593–6597.
(10) The strategy may be compared with the Au(I)-promoted spiroketali-
zation of dihydroxyalkynes: Liu, B.; De Brabander, J. K. Org. Lett. 2006, 8,
4907–4910.
(18) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. M. J. Am.
Chem. Soc. 2003, 125, 11360–11370. Connon, S. J.; Blechert, S. Angew.
Chem., Int. Ed. 2003, 42, 1900–1923.
J. Org. Chem. Vol. 74, No. 20, 2009 7775

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SCHEME 3. Synthesis of Dihydroxyalkene 5
FIGURE 2. 1H NMR analysis of 2 (d6-benzene) and 17 (d6-DMSO).
SCHEME 4. Monensin Spiroketal Analogues
the phthalate half-ester from 6, and homoallylic alcohol 7.
RCM on 12 using Grubbs II catalyst afforded 13 in 91%
yield as an inseparable 4:1 mixture of alkene isomers of
undetermined configuration. Cleavage of 13 with NaOMe
provided the required dihydroxyalkene 5 in 70% overall
yield from 7.
Iodoetherification of 5 using iodonium dicollidine per-
chlorate (IDCP) in dichloromethane provided an insepar-
able mixture of at least three iodocyclization products in the
ratio of 5:3:1 in 86% yield (Scheme 4). The complexity of the
NMR data for the iodocyclization product did not allow for
the distinction between 4 or 14. On the basis of the expected
preference for the 6-exo-trig mode of cyclization versus the
other cyclization pathways, we believe the major iodocycli-
zation product to be THP 4.19 Exposure of the iodocycliza-
tion product to silver triflate in the presence of 2,4,6-collidine
gave a 2:1 inseparable mixture of spiroketals 3 in 65% yield.
The gross structure of 3 was determined by H/H and C/H 2D
NMR, but complete stereochemical analysis was not possi-
ble at this stage because of the complexity of the spectral
data. Regarding the mechanism of the transformation of 4
(or 14) to 3, we presume that the formation of 3 proceeds via
the oxocarbenium ion 15 (or 16). The latter may arise directly
from cleavage of the C-I bond and a hydride shift, or
indirectly through dehydroiodination to an initially formed
enol ether, which is subsequently protonated.
analysis of TOCSY, NOESY, and HSQC data for 2 and 17
and their acetate derivatives in DMSO and, or benzene
solutions (Figure 2). Surprisingly the configuration of the
alcohol in the six-membered ring (i.e., at C-19) in the major
isomer 17 was found to be inverted relative to the starting
spiroketal 3. Thus, a strong NOE between H-19 and H-21
indicated a syn diaxial-like relationship between H-19 and
H-21, which meant that H-19 assumed an axial-like orienta-
tion on the six-membered ring. Large J values assigned to
J18ax,19 and J19,20ax in the signal for H-19 (δ 3.80 ppm,
To remove the MOM and orthoester protecting groups
and possibly equilibrate the spiroketal mixture in a single
step, 3 was next exposed to aqueous HCl in THF. The crude
product was completely hydrolyzed to a mixture of dihydro-
xyacids, which was treated with DCC to give a 1:3 mixture of
2:17 in a combined yield of 72% from 3. Interestingly, re-
exposure of 2 to the reaction conditions gave a similar ratio
of 2 and 17. The structures were assigned through detailed
apparent tt, J18eq,19 = J19,20eq = 4.5, J18ax,19 = J19,20ax
=
12.0 Hz) suggested a diaxial relationship between H-19 and
protons on H-18 and H-20, which corroborated the NOE
data and pointed to the chair conformation shown. Similar
J values were extracted from the H-19 signal of the derived
acetate 17-OAc (δ 5.58 ppm, apparent tt, J18eq,19=J19,20eq
=
4.8, J18ax,19 =J19,20ax =11.5 Hz). The anomeric configura-
tion at the spiroketal carbon was assigned on the basis of a
NOE between H-21 and one of the carbinol protons in the
(19) Bedford, S. B.; Bell, K. E.; Bennet, F.; Haynes, C. J.; Knight, D. W.;
Shaw, D. E. Perkin Trans. 1 1999, 2142–2153.
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Tony et al.
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tris-THF residue, presumed to be H-13. Such a NOE is not
possible for the opposite acetal configuration. Consistent with
this analysis is the absenceof any NOEs between H-19or H-21
and any of the methylene protons in the proximal THF ring.
In the case of the minor spiroketal 2, the signals for H-19
SCHEME 5. Synthesis and Stereochemical Analysis of Model
Spiroketals
(δ 4.10 ppm, apparent dquintet, J18eq,19=J18ax,19=J19,20ax
=
J19,20eq =ca. 3.8, J19,OH =10.0 Hz) and H-21 (δ 4.18 ppm,
0
apparent tdd, J20eq,21=J21,22=ca. 2.2, J21,22 =7.5, J20ax,21
=
8.0 Hz) indicated relatively small J values for H-19 and the
protons on C-18 and C-20, and a J value of 8.0 Hz between
H-21 and one of the H-20 protons. This data is in agreement
with the stereochemistry at C-19 and C-21 and the six-
membered ring conformation as illustrated. The J values for
H-19 in 2-OAc (δ 5.15 ppm, apparent quintet, J=3.0 Hz) also
supported an equatorial-like positioning of H-19. Unfortu-
nately, the NOESY data for 2 or 2-OAc were not helpful in
assigning the configuration at the spiroketal carbon. The
anomeric configuration was subsequently assigned by com-
parison with the NMR data for simpler spiroketal analogues
(vide infra).
To probe the configurational inversion observed at C-19
in the transformation of THP-iodide 4 to the spiroketal 17
and obtain simpler spiroketal analogues as reference com-
pounds for assigning the stereochemistry of 2 and 17, we
investigated the spiroketalization protocol on substrates 18
and 21 (Scheme 5). A cross metathesis strategy using an
excess of the more easily accessible alkene partner was
practical for the preparation of these precursors. These
results and the transformation of 18 and 21 to spiroketal
mixtures 19-OAc:20-OAc (3:1) and 22-OAc:23-OAc (2:1)
have been previously reported. The stereochemical assign-
ment of the spiroketal products is detailed here. For 20-OAc,
(the minor isomer from 18), a J value of 4.7 Hz for H-7 and
each of the protons at C-6 and C-8 and a NOE between H-9
and H-4 suggested an equatorial-like orientation of the
substituent at C-7 and the nonanomeric spiroketal config-
uration in the conformation shown. The configuration at
C-7 of the major isomer 19-OAc was similarly established
from J data, and the spiroketal configuration inferred, on the
assumption of its diastereomeric relationship to 20-OAc.
The deshielding of H-9 in 19-OAc by the axial anomeric
oxygen relative to the corresponding proton in 20-OAc
(δ 4.30 vs 3.70) corroborated the relative configuration at
the spiroketal carbons in 19-OAc and 20-OAc.,20 The ster-
eochemistry of 22-OAc and 23-OAc, the spiroketals from 21,
was determined in a similar fashion as described for 19-OAc
and 20-OAc. The configuration at C-7 was assigned from
vicinal J values and the configuration at the spiroketal
carbons was based on NOEs between H-9 and CH2-1 in
the major anomeric product 22-OAc. As for 19-OAc/20-
OAc, the downfield shift of H-9 in 22-OAc relative to 23-
OAc supported the assignment at the spiroketal carbons.
To assign the acetal configuration in the monensin-like
was assigned the anomeric configuration. The data for the
deacetylated analogues 2 and 19 were also in excellent
agreement. Of additional note, the 1H NMR for the alcohols
2 and 19 showed a characteristic sharp doublet for the
hydroxyl proton (i.e., δ 3.97, d, J = 10.0 Hz), which is
consistent with the intramolecular hydrogen bond that is
believed to stabilize such anomeric spiroketals with an axial
alcohol at C-19/C-7.9 Interestingly, the signals for the OH
protons were not easily discernible in the spectra of the C-19/
C-7 epimeric alcohols 17 and 22. Similarly, closer matching
of the NMR data for the other monensin analogue 17-OAc
to the model spiroketal 22-OAc compared to the anomeric
partner 23-OAc provided independent support for the con-
figuration that was earlier assigned to the spiroketal carbon
in 17-OAc.
As indicated earlier, because of difficulty in assigning
stereochemistry in 3, the product of the silver-mediated
spiroketalization of the monensin substrate 4, it was not
clear whether the loss of configurational integrity at C17 that
was observed in the transformation of 4 f 3 f 17 (and 2) had
occurred in the initial spiroketalization step or the sub-
sequent acid-mediated protecting group removal step. That
the configuration at C7 was preserved in the spiroketaliza-
tion of 18 and 21 suggests that the former is unlikely. A more
plausible explanation is that inversion at C19 occurs in the
acid-promoted reaction on 3, via an elimination-addition
sequence involving an intermediate enone I or related
1
spiroketal 2-OAc, the H and 13C chemical shifts for the
carbinols on the six-membered ring and the acetal carbon
were compared to the corresponding signals in 19-OAc and
20-OAc, the model spiroketals for the two anomers of 2-OAc
(Supporting Information). Thus the data for 2-OAc very
closely matched that for 19-OAc but not 20-OAc, and
accordingly the acetal center in 2-OAc (and therefore 2)
(20) Ireland, R. E.; Daub, J. P. J. Org. Chem. 1983, 48, 1303–1312.
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SCHEME 6. Proposed Mechanism for C-19/C-7 Epimerization
nonacidic conditions. This strategy appears especially ap-
propriate for highly functionalized substrates and may be
relevant to the formation of spiroketals under kinetic con-
ditions. However, in the present case, these features are
negated by the highly acidic conditions required to remove
the MOM protecting group in the initial spiroketal product.
Therefore the synthetic scope can be maximized by judicious
selection of alcohol protecting groups.
Experimental Section
Monensin Analogues (2 and 17). A solution of 3 (26 mg,
0.04 mmol), THF (0.8 mL) and 6 N HCl (0.2 mL) was stirred at
rt for 3 h. The reaction mixture was then adjusted to pH 5 by
addition of saturated aqueous NaHCO3 and diluted with MeOH
(0.8 mL). Aqueous 1 N NaOH (1.0 mL) was then added, and the
mixture stirred at rt for 1 h. The pH of the mixture was then
adjusted to 5 by carefully adding 3 N HCl. Most of the solvent was
evaporated under reduced pressure, and the residual solution was
extracted with diethyl ether. The ether extract was dried (Na2SO4),
filtered, and concentrated in vacuo. The crude oil was dried
by removal of the benzene-water azeotrope, and DCC (15 mg,
0.06 mmol) and DMAP (3 mg, 0.02 mmol) were added at 0 °C to
the resulting benzene solution (1 mL). The reaction mixture was
stirred for 3 h. The solvent was then evaporated in vacuo, and the
residue was purified by FCC to afford 2:17 (16 mg, 72%) in a
respective ratio of 1:3. Repeat FCC on the mixture afforded
separated samples of 2 and 17.
SCHEME 7. C7 Epimerization in Model Spiroketals
For 2: Rf=0.30 (10% MeOH/CH2Cl2); 1H NMR (500 MHz,
C6D6) δ 0.80-2.10 (m, 28H), 3.3 (t, J = 6.1 Hz, 2H), 3.75
(m, 3H), 3.90 (m, 3H), 3.97 (d, J = 10.1 Hz, 1H, OH), 4.10
(dquintet, J = 3.8, 10.2 Hz, 1H), 4.18 (app tdd, J = 2.2, 2.5,
8.0 Hz, 1H), 4,32 (s, 2H), 7.24 (m, 3H), 7.32 (d, J=7.2 Hz, 2H).
13C NMR (125 MHz, C6D6) δ 18.6, 23.2, 25.2, 28.0, 28.4, 28.6,
28.8, 28.9, 30.1, 30.7, 36.6, 39.1, 39.5, 39.6, 65.6, 65.7, 70.7, 73.3,
81.3, 81.7, 82.5, 83.1, 84.3, 107.6, 127.1-129.3 (aromatic carbons
buried in C6D6 triplet), 139.9, 169.8. ESMS (M þ NH4)þ 576.2.
For 2-OAc: Rf=0.85 (10% MeOH in CH2Cl2); 1H NMR (500
MHz, C6D6) δ 1.00-2.25 (m, 31 H), 3.40 (t, J=6.3 Hz, 2H), 3.79
(m, 2H), 3.90 (apparent q, J=6.2 Hz, 1H), 4.02 (m, 2H), 4.12
(apparent q, J=6.4 Hz, 1H), 4.31 (m, 1H), 4.45 (s, 2H), 5.15 (app
quintet, J = 3.0 Hz, 1H), 7.27 (m, 3H), 7.45 (d, J=7.2 Hz, 2H).
13C NMR (125 MHz, C6D6) δ 18.6, 21.6, 23.1, 25.3, 28.4, 28.5,
28.9, 29.0, 29.5, 30.1, 30.7, 35.6, 36.3, 36.6, 40.1, 65.4, 68.1, 70.7,
73.3, 81.3, 81.7, 82.5, 82.8, 84.0, 105.8, 127.9-128.9 (aromatic
carbons buried in C6D6 triplet), 139.9, 169.6, 170.3. FABHRMS
calcd for C34H49O9 (M þ H)þ 601.3377, found 601.3381.
oxocarbenium ion II (Scheme 6). Similar observations have
previously been reported.21 Such a mechanism is also con-
sistent with the observation that re-exposure of 2 under
similar conditions leads to a mixture of 2 and 17. To test
this hypothesis, alcohol 19 (which is stereochemically ana-
logous to 3) was subjected to the identical acidic procedure
that was applied to 3 (Scheme 7). Indeed, this reaction
produced a mixture of rearranged [5.5.0] spiroketals 24 and
25 that were epimeric at C7.
For 17: Rf=0.25 (10% MeOH/CH2Cl2); 1H NMR (500 MHz,
C6D6) δ 1.05 (m, 2H), 1.15 (m, 2H), 1.50 (m, 24H), 3.42 (t, J=
6.0 Hz, 2H), 3.85 (m, 3H), 3.95 (q, J=6.4 Hz, 1H), 4.09 (m, 3H),
4.22 (app tt, J = 5.1, 11.2), 4.50 (s, 2H), 7.25 (m, 3H), 7.40 (d, J=
7.2 Hz, 2H); 13C NMR (125 MHz, C6D6) δ 18.5, 23.3, 25.1, 28.2,
28.8, 28.9, 29.1, 29.2, 30.1, 30.7, 36.7, 39.3, 41.9, 44.1, 65.9, 69.3,
70.7, 73.3, 81.3, 81.9, 82.6, 82.8, 83.5, 83.9, 107.6, 127.7-129.4
(aromatic carbons buried in C6D6 triplet), 139.9, 170.0. 1H
NMR (500 MHz, DMSO-d6) δ 0.95 (q, 6.0 Hz, 1H, H-20ax),
1.21 (m, 1H, H-23), 1.25-1.95 (m, CH2-3, 4, 7, 8, 11, 12, 15, 16,
18, H-20eq, CH2-22, H-230, CH2-24, 24H), 2.30 (ddd, J=7.0,
9.5, 17.0 Hz, H-2), 2.45 (ddd, J=5.0, 6.0, 17.0 Hz, H-20), 3.37
(t, J=6.5 Hz, CH2-25), 3.55 (m, 1H, H-21), 3.70 (m, 2H, H-13,
14), 3.80 (tt, J=4.5, 12.0 Hz, 1H, H-19), 3.85 (m, 1H, H-9), 3.95
(m, 2H, H-6, 10), 4.30 (dt, J=3.5, 12.0 Hz, H-5), 4.37 (s, 2H,
PhCH2). FABHRMS calcd for C32H47O8 (M þ H)þ 559.3271,
found 559.3282. For 17-OAc: Rf=0.80 (10% MeOH/CH2Cl2);
1H NMR (500 MHz, C6D6) δ 1.00-2.25 (m, 31H), 3.42 (t,
J = 6.6 Hz, 2H), 3.80 (m, 1H), 3.93 (m, 2H), 4.05 (m, 3H),
4.46 (m, 2H), 5.58 (tt, J = 5.0, 11.5 Hz, 1H), 7.26 (m, 3H), 7.4
Conclusion
The pentacyclic monensin analogues 2 and 17 were pre-
pared in a convergent fashion from alkenol precursors 6 and
7. Although different with respect to the configuration of the
alcohol at the 3 position of the six-membered ring of the
spiroketal, the configuration at the acetal center in both 2
and 17 is unchanged and is in line with the anomeric effect.
This observation is relevant to the design of more finely
tuned spiroketal containing ionophores. From a synthetic
standpoint, attractive features are the alkenol precursors
(which in general may be obtained via a variety of established
stereoselective routes), the metathesis reaction for segment
coupling, and the generation of the spiroketal linkage under
(21) (a) Ikunaka, M.; Mori, K. Agric. Biol. Chem. 1987, 51, 565–571.
(b) Smith, A. B. III; Thompson, A. S. J. Org. Chem. 1984, 49, 1469–1471.
(c) Reference 8a.
7778 J. Org. Chem. Vol. 74, No. 20, 2009

Tony et al.
JOCArticle
(d, J=7.2 Hz, 2H). 13C NMR (125 MHz, C6D6) δ 18.6, 21.3,
23.1, 25.3, 28.5, 28,7, 28.9 (two signals), 29.2, 30.2, 30.6, 36.5,
37.9, 39.3, 40.3, 68.9, 69.2, 70.7, 73.3, 81.3, 81.8, 82.5, 82.7, 83.5,
83.9, 107.2, 127.0-128.9 (aromatic carbons buried in C6D6
triplet), 140.1, 169.7, 169.9. FABHRMS calcd for C34H49O9
(M þ H)þ 601.3377, found 601.3351.
were added phthalic anhydride (0.524 g, 3.54 mmol) and DMAP
(73 mg, 0.60 mmol). After 20 h the solution was filtered through a
bed of Celite, and the solvent was removed under reduced pressure.
The residue was purified by FCC to afford recovered 6 (104 mg)
and the derived monophthalate ester (344 mg, 85%). Rf =0.50
1
(30% EtOAc/petroleum ether); H NMR (500 MHz, CDCl3) δ
Spiroketal Mixture (3). AgOTf (121 mg, 0.47 mmol) was
added to a solution of 4 (90 mg, 0.12 mmol) and collidine
(0.06 mL) in anhydrous CH2Cl2 (15 mL). The reaction mixture
was stirred for 25 min at rt, poured into saturated aqueous
Na2S2O3 (10 mL), and extracted with CH2Cl2. The organic
extract was dried (Na2SO4), filtered, and concentrated in vacuo.
FCC of the residue afforded 3 (48 mg, 65%) as an inseparable
mixture (2:1). Rf = 0.36 (60% EtOAc/petroleum ether); 1H
NMR (500 MHz, C6D6) δ 1.22-2.17 (m, 28H), 3,20, 3.35
(both s, 1H, 2H respectively), 3.37 (apparent t, J = 7.0 Hz,
2H), 3.58 (m, 2H), 3.75 (m, 1H), 3.76-4.02 (m, 7H), 4.18
(m, 1H), 4.33 (m, 1H), 4.38, 4,40 (both s, 2H), 4.51, 4.73 (both
ABq, Δδ = 0.01, 0.12 ppm, J = 8.5, 6.5 Hz, 0.66H, 1.33H
respectively), 7.24 (m, 3H), 7.37 (d, J=7.0 Hz, 2H); 13C NMR
(75 MHz, C6D6) δ 22.0, 23.1, 23.3, 23.7, 27.7, 28.3, 28.7, 29.0,
29.2, 29.3, 29.4, 29.6, 30.7, 30.8, 31.0, 32.5, 36.2, 36.6, 36.8, 37.0,
37.1, 37.3, 40.2, 40.7, 55.6, 63.6, 64.9, 65.7, 70.2, 70.9, 71.0, 73.5,
77.6, 81.2, 82.4, 82.6, 82.7, 82.9, 84.1, 84.3, 95.6 (OCH2O), 106.2
(spiroketal-major), 107.8 (spiroketal-minor), 120.2 (orthoester),
127.0-130.0 (several lines buried C6D6 triplet), 140.0. FABH-
RMS calcd for C36H55O10 (M þ H)þ 647.3795, found 647.3794.
THP-Iodide (4). To a solution of 5 (85 mg, 0.13 mmol) and 4 A
MS (225 mg) in dry CH2Cl2 (18 mL) was added IDCP (100 mg,
0.21 mmol). The mixture was stirred at rt for 15 min, filtered
through Celite into saturated aqueous Na2S2O3 (20 mL), and
extracted with CH2Cl2. The combined organic phase was dried
(Na2SO4), filtered, and evaporated in vacuo. FCC of the residue
afforded 4 (86 mg, 86%) as an inseparable mixture. Rf=0.37
1.45-1.80 (m, 7H), 2.05 (m, 1H), 2.30 (m, 1H), 2.40 (m, 1H), 3.40
(s, 3H), 3.50 (m, 2H), 3.85 (m, 1H), 4.55 (ABq, Δδ=0.05 ppm, J=
10.5Hz, 2H), 4.70 (s, 2H), 5.10 (m, 2H), 5.30(m, 1H), 5.85 (m, 1H),
7.30 (m, 5H), 7.50 (m, 2H), 7.70 (m, 1H), 7.80 (m, 1H), 10.35 (br. s,
1H); 13C NMR (75 MHz, CDCl3) δ21.8, 29.5, 34.1, 38.7, 55.5, 70.0,
72.8, 73.1, 74.2, 95.2, 117.7, 127.6, 127.7, 128.3, 128.8, 129.1, 130.8,
131.3, 132.8, 134.2, 138.3, 167.6, 169.9. FABHRMS calcd for
C27H34O7Na (M þ Na)þ 493.2202, found 493.2205.
A stirred solution of alcohol 711 (200 mg, 0.56 mmol), the acid
from the previous step (335 mg, 0.713 mmol), DMAP (14 mg,
0.11 mmol), and camphorsulfonic acid (13 mg, 0.06 mmol)
in anhydrous benzene (25 mL) at 5 °C was treated with DCC
(260 mg, 1.12 mmol). After the mixture stirred for 19 h at rt,
diethyl ether (50 mL) was added, and the mixture was filtered
through Celite. Concentration of the filtrate and FCC of the
residue afforded 12 (400 mg, 90% based on recovered starting
1
material). Rf =0.58 (30% EtOAc/petroleum ether); H NMR
(500 MHz, C6D6) δ 1.59-1.98 (m, 21H), 2.21 (m, 1H), 2.49 (m,
2H), 2.69 (m, 1H), 2.75 (m, 1H), 3.26 (s, 3H), 3.37 (m, 2H), 3.59
(m, 2H), 3.74-3.97 (m, 7H), 4.10 (m, 1H), 4.38 (s, 2H), 4.60
(ABq, Δδ= 0.10 ppm, J=7.0 Hz, 2H), 5.16 (m, 4H), 5.52 (m,
1H), 5.61 (m, 1H), 6.00 (m, 2H), 7.03 (m, 2H), 7.22 (m, 3H), 7.37
(d, J=8.0 Hz, 2H), 7.73 (m, 2H); 13C NMR (75 MHz, C6D6)
δ 22.0, 22.9, 28.2, 28.5, 28.8, 28.9, 29.6, 30.6, 32.5, 35.1, 36.7,
39.7, 39.9, 55.9, 63.7, 65.0, 70.8, 73.5, 73.6, 75.2, 76.4, 77.5, 80.6,
82.3, 82.5, 83.0, 96.4, 117.8, 118.0, 120.2, 127.9, 129.4, 129.5,
130.9, 131.2, 133.6, 134.4, 134.8, 135.4, 140.0, 166.8, 167.3.
FABHRMS calcd for C46H62O12Na (M þ Na)þ 829.4139,
found 829.4136.
1
(60% EtOAc/petroleum ether); H NMR (500 MHz, C6D6) δ
1.14-2.29 (m, 26H), 3.20, 3.21, 3.25 (all s, 3H), 3.39 (m, 2H),
3.61 (m, 2H), 3.76-3.91 (m, 9H), 4.11 (m, 1H), 4.20-4.52
(m, 6H), 7.20 (m, 3H), 7.35 (m, 2H); 13C NMR (75 MHz, C6D6)
δ 21.9, 23.1, 23.1, 23.8, 26.0, 26.2, 26.4, 27.6, 27.9, 28.2, 28.3, 28.7,
28.8, 28.9, 29.3, 30.6, 30.7, 32.4, 33.8, 36.0, 36.2, 36.7, 36.8, 37.2, 37.3,
39.8, 40.1, 40.9, 41.5, 41.7, 55.6, 55.7, 63.7, 65.0, 70.2, 70.7, 71.0, 71.2,
73.1, 73.3, 73.4, 73.6, 75.0, 76.0, 76.2, 77.4, 77.4, 82.1, 82.2, 82.4, 82.6,
82.7, 83.1, 83.6, 83.7, 95.3, 95.7, 95.9, 120.1, 127.0-130.0 (several
lines buried under C6D6 triplet), 140.0. FABHRMS calcd for C36-
H57O10I (M þ H)þ 775.2918, found 775.2920.
Cyclic Alkene (13). Grubb’s II catalyst (68 mg, 0.08 mmol) in
CH2Cl2 (3 mL) was injected, at rt, into a degassed solution of
diene 12 (360 mg, 0.40 mmol) in CH2Cl2 (40 mL). The mixture
heated at reflux for 4 h and cooled to rt, at which time DMSO
(0.2 mL) was added, and stirring was continued for 16 h. The
solution was then concentrated in vacuo. FCC of the residue
afforded 13 (280 mg, 91% based on recovered starting material)
as an inseparable 4:1 mixture. Rf=0.42 (40% EtOAc/petroleum
ether); 1H NMR, major isomer, (500 MHz, C6D6) δ 1.60-1.93
(m, 20H), 2.01 (m, 1H), 2.15 (m, 2H), 2.32 (m, 1H), 2.62 (m, 2H),
3.15 (s, 3H), 3.40 (t, J=7.0 Hz, 2H), 3.58 (m, 2H), 3.74 (m, 2H),
3.86 (m, 2H), 3.95 (m, 4H), 4.40 (s, 2H), 4.48 (m, 2H), 5.48
(m, 2H), 5.58 (m, 2H), 7.01 (m, 2H), 7.23 (m, 3H), 7.38 (d, J=
Dihydroxyalkene (5). Mixed phthalate-alkene 13 (75 mg, 0.10
mmol) was dissolved in MeOH (7 mL) and a ca. 1 M solution of
NaOMe in MeOH (1.5 mL) was added. The mixture was stirred for
24 h at rt. The solvent was removed in vacuo, and the residue was
dissolved in ether. The ethereal extract was washed with brine,
dried (Na2SO4), and concentrated under reduced pressure. The
residue was purified by FCC to afford recovered starting material
13 (7 mg) and 5 (48 mg, 85% based on recovered 13). Rf =
0.13 (60% EtOAc/petroleum ether). 1H NMR (500 MHz, C6D6,
major isomer) δ1.40 (m, 3H), 1.60 (m, 4H), 1.71 (m, 8H), 1.88
(m, 6H), 2.07 (m, 1H), 2.22 (m, 1H), 2.28 (t, J=8.0 Hz, 2H), 2.35
(m, 1H), 3.03 (br s, 1H), 3.21 (s, 3H), 3.41 (m, 3H), 3.58 (m, 2H),
3.74-3.94 (m, 7H), 3.97 (m, 1H), 4.18 (m, 1H), 4.20 (m, 1H), 4.41
(s, 2H), 4.47 (ABq, Δδ=0.12 ppm, J=7.0 Hz, 2H), 5.57 (m, 1H),
5.62 (m, 1H), 7.16 (t, J=8.0 Hz, 1H), 7.24 (t, J=8.0 Hz, 2H), 7.38
(d, J=8.0 Hz, 2H); 13C NMR (75 MHz, C6D6, mixture) δ 21.9,
23.2, 25.9, 26.2*, 27.7, 28.3, 28.9, 29.2, 30.8, 32.4, 32.7*, 33.0*, 37.9,
38.7, 38.8, 42.8, 56.0, 63.7, 65.0, 70.9, 71.7, 73.5, 73.8*, 73.5, 77.4,
77.7, 82.2, 82.5, 82.8, 83.3, 95.9, 120.1, 127.9, 128.9, 129.0, 130.3,
140.0 (* indicates selected signals for minor isomer). FABHRMS
calcd for C36H56O10Na (M þ Na)þ 671.3771, found 671.3770.
Mixed Phthalate Ester (12). To a stirred solution of alkenol 6
(0.381 g, 1.18 mmol, Supporting Information) in pyridine (15 mL)
8.0 Hz, 2H), 7.61 (d, J=7.0 Hz, 1H), 7.79 (d, J=7.0 Hz, 1H); 13
C
NMR, major isomer, (75 MHz, C6D6) δ 22.0, 23.5, 28.2, 28.4,
28.6, 28.8, 29.7, 30.7, 32.5, 34.4, 35.1, 37.5, 39.6, 55.9, 63.7, 65.0,
70.9, 73.5, 74.3, 76.0, 77.5, 81.2, 82.2, 82.5, 83.0, 96.7, 120.2,
127.9, 128.9, 129.1, 129.6, 130.5, 131.8, 132.5, 136.0, 140.0,
166.3, 168.0. FABHRMS (mixture) calcd for C44H59O12 (M þ
H)þ 779.4007, found 779.4009.
Bicyclic Spiroketal Alcohol (19). K2CO3 (10 mg) was added to
a solution of 19-OAc (10.0 mg, 0.018 mmol) in methanol (1 mL).
The reaction mixture was stirred for 4 h at rt and neutralized
with methanolic HCl. The mixture was diluted with CH2Cl2,
and the suspension was filtered through Celite. The filtrate was
evaporated in vacuo, and the residue was purified by FCC to
give alcohol 19 (8.0 mg, 88%). Rf =0.25 (20% EtOAc/petro-
leum ether); 1H NMR (500 MHz, C6D6) δ 1.03-1.18 (m, 21H),
1.25 (m, 2H), 1.38 (m, 2H), 1.48 (m, 1H), 1.53 (m, 1H),
1.60-1.74 (m, 6H), 1.80 (m, 3H), 1.87 (dd, J =7.0, 10.0 Hz,
1H), 3.37 (t, J=6.2 Hz, 2H), 3.65 (dd, J=6.5, 9.6 Hz, 1H),
3.86 (dd, J=6.4, 9.6 Hz, 1H), 3.97 (d, J=10.2 Hz, 1H, OH), 4.10
(app dquintet, J=3.1, 10.2 Hz, 1H), 4.19 (app quintet, J=5.0 Hz,
J. Org. Chem. Vol. 74, No. 20, 2009 7779

Tony et al.
JOCArticle
1H), 4.23 (m, 1H), 4.38 (s, 2H), 7.20 (m, 3H), 7.34 (d, J=7.5 Hz,
2H). 13C NMR (125 MHz, C6D6) δ12.7, 18.6, 23.3, 27.3, 30.9, 36.8,
39.2, 39.3, 39.5, 65.5, 65.7, 68.6, 70.8, 73.2, 82.6, 107.6, 127.9-128.9
(aromatic carbons buried in C6D6 triplet), 139.9. ESHRMS calcd
for C29H54NO5Si (M þ NH4)þ 524.3766, found 524.3773.
δ 1.38 (m, 5H), 1.54 (m, 2H), 1.69 (m, 4H), 1.76 (s, 3H), 1.85 (s,
3H), 1.87 (dt, J=4.7, 11.7 Hz, 1H), 2.17 (tt, J=4.5, 11.5 Hz, 1H),
2.25 (dt, J=1,4, 15.0 Hz, 1H), 3.44 (t, J=6.0 Hz, 2H), 3.85 (dd,
J=1.7, 12.7 Hz, 1H), 3.90 (bd, J=1 12.7, 1H), 4.04 (m, 1H), 4.46 (s,
2H), 4.82 (bs, 1H), 5.12 (apparent q, J=3.6 Hz, 1H), 7.25 (m, 5H).
13C NMR (125 MHz, C6D6) δ 21.2, 21.5, 23.2, 23.3, 30.8, 31.2,
35.6, 36.4, 38.2, 62.6, 65.0, 67.5, 70.6, 73.4, 95.8, 127.0-129.0
(aromatic carbons buried in C6D6 triplet), 139.8, 170.3. ESHRMS
calcd for C24H34O7Na (M þ Na)þ 457.2196, found 457.2199. For
25: Rf=0.47 (25% EtOAc/petroleum ether); 1H NMR (500 MHz,
C6D6) δ 1.32 (m, 2H), 1.44 (m, 2H), 1.55 (m, 1H), 1.67 (m, 5H),
1.79 (s, 3H), 1.84 (s, 3H), 1.89 (dt, J=4.2, 13.3 Hz, 1H), 2.05 (m,
1H), 2.11 (tt, J=5.0, 13.6 Hz, 1H), 2.29 (ddd, J=2.0, 5.0, 12.1 Hz,
1H), 3.45 (m, 2H), 3.47 (m, 1H), 3.72 (ABq, Δδ= 0.16 ppm, J=
12.7 Hz, 2H), 4.47 (bs, 1H), 4.80 (bs, 1H), 5.57 (ddd, J=3.0, 9.5,
14.5 Hz, 1H), 7.25 (m, 5H). 13C NMR (125 MHz, C6D6) δ 21.0
(two signals), 23.0, 23,1, 30.2, 30.5, 36.1, 37.8, 41.3, 62.2, 67.3, 67.9,
68.5, 70.4, 73.2, 97.1, 127.0-129.0 (aromatic carbons buried in
C6D6 triplet), 169.6. ESHRMS calcd for C24H34O7Na (M þ Na)þ
457.2196, found 457.2198.
Bicyclic Spiroketal Alcohol (22). Application of the deacety-
lation procedure that was described for 19 to 22-OAc (6.0 mg,
0.011 mmol) provided alcohol 22 (5.0 mg, 91%). Rf=0.25 (20%
EtOAc/petroleum ether); 1H NMR (500 MHz, C6D6) Rf=0.25
1
(20% EtOAc/petroleum ether); H NMR (500 MHz, C6D6) δ
1.05-1.17 (m, 21H), 1.01 (m, 1H), 1.36 (m, 3H), 1.47 (m, 3H),
1.54 (m, 1H), 1.62 (m, 3H), 1.74 (m, 1H), 1.82 (m, 1H),
1.85-2.00 (m, 3H), 3.36 (t, J=6.1 Hz, 2H), 3.68 (dd, J=7.0,
9.5 Hz, 1H), 3.81 (m, 1H), 3.94 (dd, J=5.8, 9.5 Hz, 1H), 4.07
(app tt, J=4.7, 11.2 Hz, 1H), 4.24 (quintet, J=6.6 Hz, 1H), 4.37
(s, 2H), 7.12 (t, J=7.5 Hz, 1H), 7.20 (t, J=7.5 Hz, 2H), 7.33
(t, J=7.5 Hz, 1H). 13C NMR (125 MHz, C6D6) δ 12.7, 18.6,
23.3, 28.2, 30.8, 36.7, 39.1, 41.7, 43.8, 66.0, 68.8, 69.2, 70.8, 73.4,
82.0, 107.4, 128.0-128.9 (aromatic carbons buried in C6D6
triplet), 139.8. ESHRMS calcd for C29H50O5SiNa (M þ Na)þ
529.3320, found 529.3330.
Bicyclic Spiroketals (24 and 25). A solution of 19 (4.0 mg,
0.008 mmol), THF (0.4 mL) and 6 N HCl (0.1 mL) was stirred at
rt for 3 h following the identical conditions that were applied
to 3. The reaction was then diluted with saturated aqueous
NaHCO3 and extracted with ether. The ether extract was
dried (Na2SO4), filtered, and concentrated in vacuo. FCC
(80% EtOAc/petroleum ether) of the crude product afforded
two components (ratio ca. 3:1), which were individually dis-
solved in EtOAc (1 mL) and treated with acetic anhydride
(0.05 mL), DMAP (1 mg), and Et3N (0.1 mL). The reaction
mixture was quenched with MeOH and evaporated in vacuo.
FCC of the residue from the individual reactions afforded 24
(1.4 mg, 39%) and 25 (0.4 mg, 22%) respectively. For 24: Rf=
0.25 (25% EtOAc/petroleum ether); 1H NMR (500 MHz, C6D6)
Acknowledgment. This investigation was supported by
grant R01 GM57865 from the National Institute of General
Medical Sciences of the National Institutes of Health (NIH).
“Research Centers in Minority Institutions” award RR-03037
from the National Center for Research Resources of the
NIH, which supports the infrastructure and instrumentation
of the Chemistry Department at Hunter College, is also
acknowledged.
Supporting Information Available: Synthetic procedures
and characterization data, including 1H and 13C NMR and
spectra for compounds 2-7, 9-13, and 17-25. This material is
available free of charge via the Internet at http://pubs.acs.org.
7780 J. Org. Chem. Vol. 74, No. 20, 2009