Radical oxidative cyclization of spiroacetals to bis-spiroacetals: An overview

Article abstract of DOI:10.3390/90600394

The use of iodobenzene diacetate and iodine under photolytic conditions provides and efficient method for the oxidative cyclization of spiroacetals bearing an hydroxyalkyl side chain to bis-spiroacetals. An overview is provided of the use of this reaction

Full text of DOI:10.3390/90600394

Molecules 2004, 9, 394-404
molecules
ISSN 1420-3049
http://www.mdpi.org
Radical Oxidative Cyclization of Spiroacetals to
Bis-spiroacetals: An Overview
Margaret A. Brimble*
Department of Chemistry, University of Auckland, 23 Symonds St., Auckland, New Zealand.
Tel. (+64) 9-3737599 ext 88259, Fax (+64) 9-3737422.
* Author to whom correspondence should be addressed; e-mail m.brimble@auckland.ac.nz
Received: 18 December 2003 / Accepted: 3 January 2004 / Published: 31 May 2004
Abstract: The use of iodobenzene diacetate and iodine under photolytic conditions
provides and efficient method for the oxidative cyclization of spiroacetals bearing an
hydroxyalkyl side chain to bis-spiroacetals. An overview is provided of the use of this
reaction for the synthesis of several bis-spiroacetal containing natural products such as
the polyether antibiotics salinomycin and CP44,161 and the shellfish toxins, the
spirolides.
Keywords: Spiroacetals, bis-spiroacetals, oxidative radical cyclization
Introduction
Tricyclic bis-spiroacetal ring systems are present as sub-units in a diverse range of natural products
and have attracted attention from synthetic chemists due to their stereochemical complexity and
variety in their biological activity. Several reviews on the chemistry of more common bicyclic
spiroacetals have been published [1] and reviews on the chemistry of bis-spiroacetals have also been
forthcoming [2]. Many of the synthetic methods adopted for the construction of spiroacetals rely on the
control of stereochemistry at the anomeric centre being dictated by the relative thermodynamic
stability of the different isomers formed using an acid-catalysed spiroacetalisation step. The major

Molecules 2004, 9
395
isomer produced in this case is that which has the maximum number of anomeric effects with
minimum steric interactions. When these two factors work in opposite directions lower
stereoselectivity is observed. In tricyclic bis-spiroacetal systems the balance between these factors
needs careful consideration when predicting the outcome of the spiroacetalisation step as the small
differences in energy and interconversion barriers often lead to the formation of a range of isomeric
structures. We herein describe the subtle interplay of steric and electronic effects in the construction
of several bis-spiroacetal ring systems in the context of our own work using a kinetically controlled
oxidative radical cyclization rather than a thermodynamically controlled acid-catalysed cyclization to
construct the representative bis-spiroacetals. This radical cyclization approach also provides a
convenient method to access the thermodynamically less stable isomers.
Results and Discussion
Remote intramolecular free radical functionalization [3] provides an elegant method for the
construction of bis-spiroacetal ring systems from spiroacetal precursors. Our first example of this
approach [4] was the assembly of the unsaturated 6,6,5-bis-spiroacetal ring system present in the
polyether antibiotics salinomycin (1, [5]), narasin A (2, [6]), epi-deoxysalinomycin (3, [7]) and
antibiotic CP44,161 (4, [8]).
Me
Me Me
17
R
H
OH
Et
OH
9
O
O
21
HO C
2
O
O
H
O
O
20
H
Me H
Me
Me Me Et
OH
Et
salinomycin 1: R = H
narasin A 2: R = Me
Me
H
Me Me
OH
Et
OH
O
O
HO C
2
O
O
O
O
H
H
Me H
Me
Me Me Et
Et
epi-17-deoxy-(O-8)-salinomycin 3
OH
Me Me
Me
Me
CO H
2
OH
O
O
Me
OH
O
H
O
O
Et H
Me
Me Me Et
antibiotic CP44,161 4

Molecules 2004, 9
396
The four possible stereoisomers of the 1,6,8-trioxadispiro[4.1.5.3]pentadec-13-ene ring system
present in the salinomycin family of polyether antibiotics are depicted in Figure 1. Diastereomer A
represents the stereochemistry adopted by salinomycin (1) and CP44,161 (4) and has three stabilizing
anomeric effects but exhibits unfavourable 1,3-dipole-dipole interactions. 21-epi-salinomycin B has
only one anomeric effect and is the thermodynamically least stable diastereomer. The 17-epi-
diastereomer C exhibits three anomeric effects and although it exhibits unfavourable 1,3-diaxial
interactions between the C17 oxygen atom and the C21 methylene it lacks the unfavourable 1,3-dipole-
dipole interactions exhibited by diastereomer A and 17-epi-21-epi-diastereomer D. This qualitative
analysis leads to the assumption that 17-epi-diastereomer C exhibits the most thermodynamically
stable configuration. It transpires that in the cyclic structure that salinomycin (1) adopts, the repulsive
1,3-dipolar interactions in diastereomer A are compensated for by a hydrogen bond between the C9
and C20 hydroxy groups. Bis-spiroacetals whose structures preclude this remote hydrogen bond do not
adopt the salinomycin configuration A.
Figure 1
Me
Me
Me
17
21
17
21
2
O
R
O
Me
O
O
Me
1
O
O
R
1
R
2
Me
B
R
A
21-epi-salinomycin, 21-epi-CP 44,161
salinomycin, CP 44,161
1 anomeric effect
3 anomeric effects
dipole-dipole unfavourable
1
R
O
Me
O
1
R
Me
O
2
R
Me
O
Me
2
17
21
R
O
O
17
21
Me
Me
D
C
17-epi-salinomycin, 17-epi-CP44,161
17-epi-21-epi-salinomycin, 17-epi-21-epi-CP 44,161
3 anomeric effects
3 anomeric effects
dipole-dipole unfavourable

Molecules 2004, 9
397
During initial model studies directed towards the synthesis of salinomycin (1) it was observed that
irradiation of spiroacetal alcohol 5 in the presence of iodobenzene diacetate and iodine yielded a 2.5:1
separable mixture of the major trans bis-spiroacetal 6 together with the minor cis isomer 7 in 81%
yield (Scheme 1). The trans isomer is stabilized by only three out of the four possible anomeric effects
but is the thermodynamically isomer due to the absence of unfavourable 1,3-dipole interactions
between carbon-oxygen bonds on the central ring [9].
Scheme 1
Me
Me
Me
Me
OH
O
Me
Me
O
O
O
PhI(OAc)
+
2
O
H
I , hυ
O
O
O
2
cis
trans
5
6 58%
7 23%
In light of the fact that the major isomer obtained in this model oxidative cyclization was the trans
isomer 6 which has the same stereochemistry as that present in epi-deoxysalinomycin (3) we embarked
on the synthesis of this polyether antibiotic using this methodology. Union of lactone 8 with acetylene
9 provided the key cyclization precursors 10 and 11 bearing an iodomethyl group for further
elaboration of the resultant bis-spiroacetals 12 and 13 (Scheme 2). The key oxidative cyclization was
then achieved upon irradiation of either iodohydrin 10 or iodohydrin 11 in a solution of cyclohexane,
containing iodine and iodobenzene diacetate affording the trans bis-spiroacetal 12 and the cis bis-
spiroacetal 13 in a ratio of 1.7:1 [10]. This outcome may be explained by the proposed mechanism
wherein both diastereomeric precursors 10 and 11 form the same carbocation intermediate 14 (derived
from the corresponding free radical), that is subsequently trapped predominantly from the least
hindered α-face, to give the trans bis-spiroacetal 12 as the major product.
Pleasingly the major isomer obtained from the above radical induced oxidative cyclization had the
same trans stereochemistry as that present in epi-17-deoxysalinomycin (3). We therefore set about
appending the terminal tetrahydropyran E ring to this key bis-spiroacetal intermediate 12. After
considerable effort we were forced to abandon this work due to the incompatibility of the sensitive bis-
spiroacetal moiety with a key ring expansion reaction planned for introduction of the tetrahydropyran
E ring [11]. We therefore turned our attention to the synthesis of the related antibiotic CP44,161 4 that
contained a terminal tetrahydrofuran ring whose synthesis did not require recourse to this ring
expansion step.

Molecules 2004, 9
398
Scheme 2
Me Me
Me
OTs
OP
OSiMe
+
3
OSiMe
3
O
O
H
9
Et
8
t
P = Si BuPh
2
ref. 10
+
R
Me
O
R
Me
O
Me
I
Me
H
I
OH
O
O
H
OH
Me
Me
10
11
1 : 1
PhI(OAc) , I , hυ
2
2
R
Me
O
Me
I
+
OH
O
Me
14
R
Me
O
R
Me
I
Me
O
O
Me
I
+
O
O
O
Me
Me
13
12
1.7:1
54%
Assembly of the bis-spiroacetal core of antibiotic CP44,161 (4) was effected using methodology
previously applied to the synthesis of the bis-spiroacetal moiety of epi-17-deoxy-(O-8)-salinomycin
(3), starting from acetylene 15 and lactone 8 as used previously (Scheme 3). Addition of the lithium
acetylide derived from acetylene 15 to lactone 8 followed by treatment of the intermediate lactol with
methanol and Amberlite IR 118 resin effected hydrolysis of the acetonide group and formation of more
stable methyl acetals as a mixture of diastereomers that were not separated.

Molecules 2004, 9
399
Scheme 3
Me Me
O
OSiMe
Me
i. BuLi,-78 ,THF
ii.MeOH, Amberlite
40 %
3
OP
+
O
15
o
Me
O
Et
O
H
n
8
Me
Et
t
P = Si BuPh
2
Me
Me
PO
OSiMe
Me
3
O
H
OMe
OH
OH
Et
16
Et
i. Ac O, Et N, 96%
2
2
3
ii. H , Lindlar, EtOAc
iii. PPTS, CH Cl
2
2
R
R
Me
Me
Me
+
O
H
O
OAc
OH
Et
O
O
OAc
H
Me
Me
1:1 mixture
OH
Et
Me
18
17
85%
t
R = -CH(Et)CH OSi BuPh
2
2
PhI(OAc) , I , hυ
2
2
R
Me
R
Me
O
Et
Me
H
OAc
+
O
O
OAc
O
O
17
O
Et
Me
Me
Me
20
19
epimerization
at C-17
41%
3.3 : 1
Me
O
Me
17
O
Me
O
R
Et
OAc
21

Molecules 2004, 9
400
Protection of the primary hydroxyl group as an acetate allowed ready purification of the acetates
by flash chromatography. Partial hydrogenation of the alkyne 16 to a cis-olefin followed by acid
catalyzed cyclization resulted in a 1:1 mixture of spiroacetals 17 and 18 that were inseparable by flash
chromatography. This initial spirocyclisation is carried out under thermodynamically controlled
conditions such that the most stable configuration is afforded at the newly formed spiro centre owing
to maximum stabilization by the anomeric effect. The two isomeric spiroacetals 17 and 18 therefore
only differ in the position that the side chain adopts.
Spiroacetals 17 and 18 were treated with iodobenzene diacetate and iodine to afford a 3.3:1
mixture of tricyclic bis-spiroacetals 19 and 20. The preference for cis bis-spiroacetal 19 in this
cyclisation reaction can be attributed to the presence of the additional methyl group in the
tetrahydrofuran ring, which causes unfavourable steric interactions upon formation of the minor trans
bis-spiroacetal 20. Trans bis-spiroacetal 20 therefore undergoes rapid epimerisation at the allylic
spirocentre to cis bis-spiroacetal 21. The presence of the additional methyl group exhibited a marked
effect on the stereochemical outcome of the oxidative cyclisation in that the oxidative cyclisation of
the related spiroacetals 10 and 11 which lack this additional methyl group provided the trans isomer as
the major product (Scheme 2).
The major bis-spiroacetal 19 isolated from this oxidative cyclisation has the 17-epi-21-epi-
salinomycin stereochemistry (Figure 1) whereas the minor cis isomer 21 has the correct bis-spiroacetal
stereochemistry for salinomycin (1) and CP44,161 (4). Given that it is well established that long range
hydrogen bonding in the final molecule can dramatically alter the position of the bis-spiroacetal
equilibrium, it was envisaged that thermodynamically controlled cyclization after the whole carbon
skeleton of the natural product has been assembled, will allow convergence of the bis-spiroacetal
stereochemistry to that depicted in cis isomer 21.
The successful use of an intramolecular radical cyclization strategy to construct the five membered
ring of the 6,6,5-bis-spiroacetal moiety of the polyether antibiotics epi-17-deoxy-O-8-salinomycin (3)
and CP44,161 (4) prompted us to extend this methodology to the synthesis of the novel 6,5,5-bis-
spiroacetal present in the shellfish toxins, spirolide B (22) and D (23).
Spirolides B (22) and D (23) are members of a novel family of marine macrolides isolated from
mussels (Mytilus edulis) and scallops (Placopecten magellanicus) during routine monitoring for
diarrhetic shellfish toxins in Nova Scotia, Canada in 1995 [12]. They induce characteristic symptoms
in the mouse bioassay possibly through muscarinic acetylcholine receptor antagonism and are weak
activators of L-type transmembrane Ca2+ channels. The relative and absolute stereochemistry has not
been established to date, but a tentative assignment based on NMR studies has been reported [13]. In
common with the pinnatoxins [14], the spirolides possess a seven-membered spiro-linked cyclic imine
together with the novel 1,7,9-trioxadispiro[4.1.5.2]tetradecane bis-spiroacetal ring system.

Molecules 2004, 9
401
Me
1
R
32
31
41
N
28
24
5
7
H
O
22
O
1
O
3
2
Me
Me
HO
18
19
10
Me
15
O
13
O
OH
Me
12
2
R
1
2
Spirolide B 22: R =H, R =Me
1
2
Spirolide D 23: R =Me, R =Me
The 6,5,5-bis-spiroacetal unit of the spirolides B (22) and D (23) is challenging due to the presence
of two five-membered rings, for which the anomeric effect is considerably reduced as compared with
six-membered rings. It was envisaged that the two spiroacetal centres in the key bis-spiroacetal
fragment 24 provide an excellent synthetic target for using an iterative oxidative radical cyclisation
strategy to construct the two five-membered rings in a stepwise fashion (Scheme 4).
Scheme 4
OH
H
o
)2B
BF .Et O, THF, -78 C
3
2
t
+
Ph BuSiO
t
2
Ph BuSiO
O
then 2.5 M NaOH, H O ,
2
2
2
Me
Me
o
45 C, 1 h 82%
25
OSiEt
OSiEt
i. Et SiCl, imid,
3
3
Dess-Martin
Periodinane
3
DMAP, CH Cl 92%
H
2
2,
t
t
Ph BuSiO
Ph BuSiO
2
2
90%
ii. BH -Me S, THF
3
2
2
Me OH
O
Me
O
then H O , NaOH, 77%
2
26
O
O
OSiEt
3
OR
BrMg
t
PhI(OAc)
2
Ph BuSiO
27
2
O
t
I , hυ
Ph BuSiO
2
2
Me
OH
64%
90%
Me
R = SiEt
29: R = H
28
3
HF, py
t
Ph BuSiO
2
O
*
PhI(OAc)
2
O
I , hυ
2
*
Me
O
83%
24
4 diasteromers 1 : 1 : 1 : 1
pTSA, CH Cl
2
2
3 : 1 : 0.9 : 0

Molecules 2004, 9
402
Formation of oxaspiro rings by hydrogen abstraction promoted by hypervalent iodine led to the
spirocyclization precursors 28 and 29 as an effective strategy for the synthesis of the key 6,5,5-bis-
spiroacetal 24 present in compounds 22 and 23. Aldehyde 26 provided the substituents required for
the substituted tetrahydrofuran ring of the 6,5,5-bis-spiroacetal ring system and these were introduced
in a stereocontrolled manner by crotyl metallation of a protected 3-hydroxypropanal that afforded the
desired homoallylic alcohol 25 in 82% yield and >97% d.e. The R,R configuration was selected both
by analogy with pinnatoxin A [14] and the relative stereochemistry of the spirolides proposed by Falk
et al [13]. The resultant homoallylic alcohol 25 was then converted into aldehyde 26 in good yield
using standard transformations. The synthesis of aldehyde 26 is also flexible enabling access to bis-
spiroacetals of varying relative and absolute stereochemistry by the appropriate choice of chiral crotyl
borane used to prepare the homoallylic alcohol intermediate 25. Coupling of aldehyde 26 with the
Grignard reagent 27 proved problematic. Standard Grignard reaction conditions failed to yield the
desired product and only mediocre yields were obtained using an organolithium species derived from
the analogous iodide. Alcohol 28 was finally prepared reproducibly in 64% yield using Barbier
conditions in diethyl ether, together with the undesired Wurtz coupling product of 27. Cyclisation of
28 using iodobenzene diacetate and iodine with irradiation afforded spiroacetal 29 in 90% yield after
removal of the triethylsilyl ether by portionwise addition of HF·pyridine over several hours. Finally,
bicyclic spiroacetal 29 underwent smooth radical oxidative cyclisation to a 1:1:1:1 mixture of the four
possible diastereomers of bis-spiroacetal 24 upon treatment with iodobenzene diacetate and iodine with
irradiation. Prolonged stirring of the initial 1:1:1:1 product mixture with a catalytic quantity of
p-toluenesulfonic acid in dichloromethane gave a 3:1:0.9 mixture (24a:24b:24c, Figure 2) of three of
the four possible isomers and these were then separable by careful chromatography [15].
Figure 2
t
t
Ph BuSiO
Ph BuSiO
2
O
2
O
O
O
O
Me
24a
Me
24b
O
trans/syn
cis/syn
t
t
Ph BuSiO
Ph BuSiO
2
2
O
O
O
O
O
Me
24d
Me
24c
O
trans/anti
cis/anti
Note: The cis/trans notation refers to the arrangement of oxygens across the central ring
and syn/anti to the arrangement of the central oxygen and the alkyl substituent,
respectively.

Molecules 2004, 9
403
The stereochemistry assigned to the bis-spiroacetal isomers 24a-c was assigned on the basis of 2D
NMR and ab initio molecular modeling [15] and it was satisfying that the major bis-spiroacetal isomer
24a had the same stereochemistry as that assigned by NMR spectroscopy to the bis-spiroacetal ring
system of spirolides B (22) and D (23) [13]. Notably the initial oxidative radical cyclizations did not
provide any stereocontrol in the initially formed isomeric mixture of 1,7,9-trioxadispiro[4.1.5.2]-
tetradecanes supporting the concept that control of stereochemistry in systems containing two five-
membered rings is more problematic than similar bis-spiroacetals containing six-membered rings.
Conclusions
A summary of the use of radical initiated oxidative cyclization using iodobenzene diacetate and
iodine as a key step to prepare several biologically active natural products containing a bis-spiroacetal
unit has been presented. The stereochemistry of the bis-spiroacetal products obtained is dependent on
the nature of the cyclization precursor and introduction of substituents (as small as a methyl group)
onto the initial bicyclic spiroacetal ring can have a significant effect on the stereochemistry of the
cyclization products produced.
References and Notes
1. For reviews of spiroacetal synthesis see: (a) Kluge, A. F. Heterocycles 1986, 24, 1699; (b) Boivin,
T. L. B. Tetrahedron 1987, 43, 3309; (c) Perron, F.; Albizati, K. F. Chem. Rev. 1989, 89, 1617; (c)
Jacobs, M. F.; Kitching,W. B. Curr. Org. Chem. 1998, 2, 395; (d) Mead, K. T.; Brewer, B. N.
Curr. Org. Chem. 2002, 6, 1.
2. Brimble, M. A.; Fares, F. A. Tetrahedron 1999, 55, 7661; (b) Brimble, M. A. Cur. Org. Chem.
2003, 7, 1461.
3. For a recent review see: Majetich, G.; Wheless, K. Tetrahedron 1995, 51, 7095.
4. Baker, R.; Brimble, M. A. J. Chem. Soc., Perkin Trans. 1 1988, 125.
5. H. Kinashi, H.; Otake, N.; Yonehara, H.; Sato, S.; Saito, Y. Tetrahedron Lett. 1973, 4955.
6. Berg, D. H.; Hamill, R. L. J. Antibiot. 1978, 30, 610.
7. Westley, J. W.; Blount, J. F.; Evans, Jr. R. H.; Liu, C. J. Antibiot. 1977, 30, 610.
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Chappel, L. R.; Moppett, C. E.; Jefferson, M. T.; Celmer, W. D. Abstract 171, 18th ICACC
Meeting, Atlanta, Georgia, 1978.
9. Baker, R.; Brimble. M. A.; Robinson, J. A. Tetrahedron Lett. 1985, 26, 2115.
10. Brimble. M. A.; Williams, G. M. J. Org. Chem. 1992, 57, 5818.
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Chem. Soc., Chem. Commun. 1995, 2159.
13. Falk, M.; Burton, I. W.; Hu, T.; Walter, J. A.; Wright, J. L. C. Tetrahedron 2001, 57, 8659.

Molecules 2004, 9
404
14. Uemura, D.; Chuo, T.; Haino, T.; Nagatsu, A.; Fukuzawa, S.; Zheng, S.; Chen, H. J. Am. Chem.
Soc. 1995, 117, 1155.
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2004 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.