Consequences of acid catalysis in concurrent ring opening and halogenation of spiroketals

Article abstract of DOI:10.1021/ol991078r

(formula presented) Lewis and/or Bronsted acid additives permit ring opening and halogenation of spiroketals at substantially reduced temperatures to produce ω-iodo enol ethers in improved yield and purity, which can undergo further reaction in the presen

Full text of DOI:10.1021/ol991078r

ORGANIC
LETTERS
1
999
Vol. 1, No. 11
815-1818
Consequences of Acid Catalysis in
Concurrent Ring Opening and
Halogenation of Spiroketals
1
1
Thomas G. LaCour,* Zhiwei Tong, and Philip L. Fuchs*,†
Department of Chemistry, Purdue UniVersity, West Lafayette, Indiana 47907
lacour@purdue.edu
Received September 22, 1999
ABSTRACT
Lewis and/or Bronsted acid additives permit ring opening and halogenation of spiroketals at substantially reduced temperatures to produce
ω-iodo enol ethers in improved yield and purity, which can undergo further reaction in the presence of distal electrophilic centers to give new
steroid skeletons.
The derivation of structurally or biologically interesting
molecules from common steroids is of continued interest to
the synthetic community. As part of our ongoing program
base enhanced both the rate of reaction and the ratio of iodide
to chloride products. The latter is of practical consequence
to our purposes since conversion of 26-chlorides to the
requisite terminal alkenes has proved unrewarding under a
2
occasioned by the structural challenges and extreme antitu-
mor activity of cephalostatin bis-steroidal marine products,
we have sought the efficient construction of all of the
subunits of these antineoplastics from commercially available
4
wide variety of protocols. Although the temperature require-
ments of this system for opening the hindered, stable
spiroketal moiety of iso-sapogenins such as hecogenin acetate
1 was also improved (130-140 °C) in relation to that of
3
hecogenin acetate 1. Selective functionalization of the E-F
5
rings and reorganization of the spiroketal fusion is funda-
previous methods (180-240 °C), we were hopeful that other
mental to this goal.
In a previous communication,we reported one-step access
to intermediates such as 2 by treatment of 1 or other steroidal
Lewis or Bronsted acid catalysis might offer further
amelioration in order to extend the reaction to highly
5
d
(4) (a) DBU, KOtBu, Ag2O, etc. gave substitution byproducts, as did
spiroketals with Ph
3
2
P‚X /base in chlorocarbon solvent under
TIPSOK: Soderquist, J. A.; Vaquer, J.; Diaz, M. J.; Rane, A. M.; Bordwell,
F. G.; Zhang, S. Tetrahedron Lett. 1996, 37, 2561. (b) Exchange was
sluggish (e.g. NaI/3-pentanone/105 °C) and degraded 2a.
1
essentially neutral conditions (Scheme 1). In the case of
iodides such as 2a, we noted that minimizing the amount of
(5) (a) Dauben, W. C.; Fonken, G. J. J. Am. Chem. Soc. 1954, 76, 4618.
(
b) Cameron, A. F. B.; Evans, R. M.; Hamlet, J. C.; Hunt, J. S.; Jones, P.
†
e-mail: pfuchs@purdue.edu.
G.; Long, A. G. J. Chem. Soc. 1955, 2807. (c) Jeong, J. U.; Fuchs, P. L.,
J. Am. Chem. Soc. 1994, 116, 773. (d) Reaction with Ac2O, for example,
required ∼240 °C, but use of a catalyst (e.g., AlCl3, pyr‚HCl) permitted
complete reaction at 180 °C (refs a-c and references therein).
(6) All new compounds gave satisfactory NMR, MS, and HRMS or
combustion analysis. X-ray data for 4 (needles from EtOAc, mp 70-73
°C, 2:1 NMR ratio of epimers) Cambridge Crystallographic Data Centre
[CCDC 136164] C28H38O3; unit cell parameters a 13.4662 (18), b 12.613
(3), and c 14.726 (2) Å, â 105.497 (13)°, space group P21. Halides 2/10
prepared in this work were identical by NMR and TLC to that in ref 1
except for chloride content.
(
1) Cephalostatin Support Studies. 18. For paper 17, see: LaCour, T.
G.; Fuchs, P. L. Tetrahedron Lett. 1999, 40, 4655.
2) (a) Kuroso, M.; Kishi, Y. J. Org. Chem. 1998, 63, 6100. (b) Betancor,
C.; Dorta, R. L.; Freire, R.; Martin, A.; Prange, T.; Suarez, E. J. Org. Chem.
(
1
2
998, 63, 6355. (c) Corey, E. J.; Stoltz, B. M. Tetrahedron Lett. 1999, 40,
061.
(3) (a) LaCour, T. G.; Guo, C.; Bhandaru, S.; Boyd, M. R.; Fuchs, P. L.
J. Am. Chem. Soc. 1998, 120, 692. (b) Kim, S.; Sutton, S. C.; Guo, C.;
LaCour, T. G.; Fuchs, P. L. J. Am. Chem. Soc. 1999, 121, 2056. (c) Jeong,
J. U.; Guo, C.; Fuchs, P. L. J. Am. Chem. Soc. 1999, 121, 2071.
1
0.1021/ol991078r CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/28/1999

Scheme 1
functionalized or sensitive substrates. In this Letter, we
The presence of other acids did permit lower reaction
temperatures, but 2a was not cleanly produced. Various
additives were examined in catalytic and stoichiometric or
describe the effects of such acids and of added or alternate
sources of iodide on the course of concurrent spiroketal
opening and halogenation.
4
excess quantities. For example, TiCl at 0 °C induced no
Reactions of 1 with Ph
3
P‚I
0.8 equiv) of soluble nonnucleophilic amine (imidazole,
,6-lutidine, DBMP) evidenced new high R compounds
2
using less than a minimum
reaction, but several products including traces of 2a formed
at 25-37 °C (entries 6 and 7). No reaction occurred with
1
(
2
excess BF
85 °C to new products 5 (entry 8).
3
2
‚OEt at 25 °C, but 1 was smoothly converted at
f
6
,8
whose proportion increased rapidly with the decrease in
available base (entries 1-5, Table 1). We ascribe this
diversion to the presence of free HI, which was evident in
the vapor above the reaction mixture. Insoluble bases such
as PVP, lithium or sodium hydrides, and all alkali metal
carbonates led to similar results. We have identified the
In each of these cases, formation of both 3 and chloride
2b was reduced. Minimizing 2b by including sources of
additional iodide afforded mainly Pyhrric victories. Excess
LiI (10 equiv) permitted, for the first time, complete reaction
with stoichiometric Ph
3
2
P‚I /base, but afforded 2a, 3, 4, and
6
majority of these products as new aromatic steriods 4 (a
several unidentified compounds (entry 9). Less LiI led to
2:1 ratio of C25 epimers), which can obtained in good yield
fewer side products but increased amounts of 2b. Similar
by foregoing the use of base altogether (entry 5). Single-
crystal X-ray analysis confirmed that 4 resulted from a deep-
seated backbone rearrangement. This skeleton is suggestive
4
results were obtained with NaI or LiClO , indicating the role
of alkali metal counterion as Lewis acid. Surprisingly,
addition of non-Lewis acidic tetrabutylammonium iodide
enhanced the rate but gave exclusively 2b in excellent yield
7
of the South units in cephalostatins 5 and 6, which have
likewise sacrificed C18 to achieve aromaticity.
2
(entry 10). Use of a 20% excess of I offered a slightly
Table 1. Conditions for Reaction of 1 To Give Products 2-5
equiv of
Ph3P‚I2/basea
temp,
°Ca
entry
additive
solventa
TCE
TCE
TCE
TCE
TCE
time
1 h
0.5 h
3 h
20 min
10 min
2 (I/Cl ratio)b
67% (5:1 a /b)
75% (7:1 a /b)
8% (b only)
15% (a only)c
50% (a only)c
trace (a only)
trace (a only)
trace (a only)
trace (a only)
23% (a only)
93% (b only)
82% (8:1 a /b)
trace (a only + 70% sm)c
6% (a only)
3b
4b
5b
1
2
3
4
5
2.0/2.0 lutidine
2.0/0.8 lutidine
2.0/0.8 lutidine
2.0/0.5 lutidine
1.1/none
140
140
140
140
140
25%
18%
87%
20%c
5%c
40%c
10%c
70%
trace
trace
1
5 min
10%
6
7
8
9
2.0/1.0 DBMP
2.0/1.0 DBMP
2.0/1.0 DBMP
1.1/1.0 lutidine
2.0/2.0 lutidine
2.0/0.8 lutidine
none
1 equiv of TiCl4
1.7 equiv of TiCl4
4 equiv of BF3‚OEt2
10 equiv of LiI
10 equiv of Bu4NI
0.2 equiv of I2
DCM
DCM
DCE
TCE
TCE
TCE
DCM
DCM/CH3CN
25
37
85
140
140
140
42
24 h
24 h
0.5 h
2.0 h
0.5 h
1 h
20%c
trace
28%
40%c
80%
trace
trace
22%
6%
1
1
1
1
0
1
2
3
11%
10 equiv of HI
2 equiv of HBF4/
2 d
2 d
5%c
15%c
78%
none
25
1
0 equiv of LiI
a
DBMP ) 2,6-di-tert-butyl-4-methylpyridine; TCE ) 1,1,2,2-tetrachloroethane; DCM ) dichloromethane; DCE ) 1,2-dichloroethane. All reactions are
b
0
.1 M in 1 and use preheated baths. Isolated yields unless noted; halide ratios determined by NMR. c Yields estimated by NMR.
1816
Org. Lett., Vol. 1, No. 11, 1999

improved yield and 2a/b ratio but required extra time (a 20
min induction period was noted, entry 11). Reaction of 1
complexed alkoxy moiety faster than hydride transfer occurs.
Exposure of 1 at 25 °C to any of a variety of acids (HI,
with HI alone proved very sluggish even at 42 °C, but 5
4 3
HBF , CSA) induced epimerization in neither CH CN nor
chlorinated solvents. Previous investigations have demon-
6
formed slowly at 25 °C using LiI/HBF
Similar results were obtained with LiI/BF
4
(entries 12 and 13).
‚OEt
3
2
. Thus,
strated that C25 integrity is also retained at 25 °C with HBr
1
1
judicious choice of reaction parameters induced 1 to provide
any of compounds 2-5 in good to excellent yield.
The acid promoters herein likely encourage first-step
in AcOH.
A plausible mechanism for the production of 4 and 5 is
outlined in Scheme 2. The ω-halo enol ether 2 is the first
C22-O26 cleavage rather than the prior C26 iodide attack
1
(C26-O26 cleavage) postulated for neutral conditions.
Strong mineral acids have been considered unsuitable as
catalysts for opening steroidal spiroketals due to internal
redox-mediated C25 epimerization in polar solvent. A 1,5
Scheme 2
9
hydride transfer from the initial oxacarbenium ion affords
enolizable aldehyde A, from which the diastereomeric
spiroketals derive. This reversible hydride transfer forms the
basis of stereoselective Lewis acid promoted spiroketal
reductions which trap A upon formation.1
0
In chlorocarbon solvent, we likewise observed loss of
stereochemical integrity at 140 °C, but epimerization of 1
appears suppressed at 85 °C in the presence of the iodinating
8
reagent, which may trap the protonated or Lewis acid
(
7) Pettit, G. R.; Kamano, Y.; Dufresne, C.; Inoue, M.; Christie, N.;
Schmidt, J. M.; Doubek, D. L. Can. J. Chem. 1989, 67, 1509.
8) (a) 5 was obtained as a 3:1 mixture (NMR) of diastereomers. H and
1
(
1
3
C NMR are consistent with C20 epimers: positions 11, 18, 19-21, 26,
1
and 27 all show minor peaks [e.g., H NMR (CDCl3, 300 MHz) δ major
product detected in all these reactions. Bronsted or Lewis
acid activation of 2a permits C16 substitution with E-ring
opening, leading to products derived from ω,ω′-diiodo-22-
ketone 6 when an aldol acceptor functionality (e.g., the C12
ketone) is available. At lower temperatures, the reaction halts
at diiodo enone 5. Prior C25 epimerization of 1 leads to the
corresponding 2aE and 5E diastereomeric mixtures. High
temperatures apparently provide sufficient energy for elimi-
nation of the 16-iodide from 5E, migration of the resulting
(
3.15, dd, J ) 9.6, 5.3, H26b; 2.72, dd, J ) 12, 4.4, H11R; 0.87, d, J ) 6,
H27), minor (3.09, dd, J ) 9.6, 5, H26b; 2.82, dd, J ) 13, 4.6, H11R; 0.85,
d, J ) 6, H27)] in similar ratios. 25(R) iodides prepared under neutral
conditions in (ref 1) such as 2a [3.24, dd, J ) 9.6, 4.3, H26a; 3.14, dd, J )
9
.6, 5.7, H26b; 2.22, dd, J ) 13.6, 5, H11R; 0.99, d, J ) 6.2, H27] and 10a
[
3.24, dd, J ) 9.6, 4.2, H26a; 3.14, dd, J ) 9.6, 5.5, H26b; 1.00, d, J ) 6.5,
H27] are distinguishable from 25(S) iodides, e.g., from sarsasapogenin (ref
1
)
1
13a [3.20, dd, J ) 9.7, 4.0, H26a; 3.14, dd, J ) 9.7, 5.9, H26b; 0.96, d, J
5.4, H27]), and none showed minor peaks as in 5. 2a from entry 8, Table
, appears to be >98% diastereomerically pure as judged by conversion to
and comparison to 3 prepared in ref 1.
3
(
9) (a) Callow, R. K.; James, V. H. T. J. Chem. Soc. 1955, 1671. (b)
Wall, M. E.; Serota, S.; Witnauer, L. P. J. Am. Chem. Soc. 1955, 77, 3086.
c) Woodward, R. B.; Sondheimer, F.; Mazur, Y. J. Am. Chem. Soc. 1958,
1
5
16
∆
or ∆ bond, and loss of C18 (probably as MeI) to
(
achieve aromaticity in 4.
8
1
0, 6693. (d) Deslongchamps, P.; Rowan, D. D.; Pothier, N. Can. J. Chem.
981, 59, 2787.
(
10) Fukuzawa, S.; Matsunaga, S.; Fusetani, N. J. Org. Chem. 1997,
(11) Callow, R. K.; James, V. H. T.; Kennard, O.; Page, J. E.; Paton, P.
N.; di Sanseverino, L. R. J. Chem. Soc. C 1966, 288.
6
2, 4484 and references therein.
Org. Lett., Vol. 1, No. 11, 1999
1817

Scheme 3
solvent (eqs 1 and 2). Acid (or excess I
2
) may suppress such
P‚I ” (or
2
P‚I , the actual form of the reagent
Although the putative diketone 6 was not observed, the
reaction of the simple 6,6-spiroketal 7 helped illuminate
structural influences on the course of these reactions (Scheme
competition and maximize the effective “Ph
3
2
+
-
14
Ph
3
PI I
3
, or base‚Ph
3
is not clear).
3
). No reaction of 7 with the Ph
3
2
P‚I /base reagent occurred
at 25 °C, and only slow conversion was noted in DCM/CH
3
-
CN at 60 °C. However, complete consumption of 7 proceeds
smoothly at 80 °C to afford a 70% yield of unexpected
6
products 8. Presumably, the unhindered ω-halo enol ether
products derived from 7 undergo subsequent reaction to give
ω,ω′-dihalo ketones 8. In the absence of reactive distal
functionality, such a product is isolable.
No diidoketone analogous to 6 (Scheme 1) or 8 (Scheme
) was confirmed from 9 under conditions (excess BF ‚OEt
as in entry 9, Table 1) which gave 5 from 1, although several
The absence of a C12 electrophilic center in rockogenin
diacetate 9 was expected to render the substrate compatible
3
3
2
with acid catalysis. In the event, reaction of 9 with Ph
3
P‚
/base alone in TCE required 130-140 °C, but addition of
stoichiometric BF ‚OEt permitted smooth conversion to 10a/
b in high yield at 85 °C (refluxing DCE, Scheme 3, reaction
B). Use of nonchlorinated solvent (CH CN, reaction A) to
avoid formation of chloride 10b gave multiple products with
even catalytic BF ‚OEt , and further solvent studies were
rendered superfluous by the near absence of 10b (5%) in
as yet unidentified products were observed in addition to
1
I
2
10a (30%, no 10b). For 9, and likely for any steroid without
3
2
additional acid-labile moieties, spiroketal conversion to
ω-iodo enol ethers such as 10a which are wholly free of
chlorides can also be accomplished (slowly) at 25 °C in good
yield under the influence of combined Bronsted and Lewis
acid catalysis (HBF /LiI, reaction C). It should be noted that
4
HI alone or HI with added LiI gave extremely sluggish
reaction with 9, as had been seen for 1.
In conclusion, Lewis and/or Bronsted acid promotion of
concurrent ring opening and halogenation of spiroketals
permits lower reaction temperature than is required under
neutral conditions and minimizes diversion to chloride and
cyclohexanone side products. Substrates such as 9 without
a C12 ketone appear amenable under these conditions to
clean production of stable ω-iodo enol ethers, whereas 1
gives iodo enol ether 2a which can react to furnish new
steroid skeletons. Further experiments along these lines are
in progress which we hope will identify a lower temperature
protocol compatible with acid-sensitive substrates such as
6
3
3
2
1
2
the DCE reaction. We note that the mixing order in A-C
Ph P added to a solution of 9 followed by iodine, base, then
Lewis acid) differs from that adopted for “neutral” conditions
(
3
1
(
substrate, Ph
mixtures were nearly colorless until complete dissolution of
, when a pale orange color arose which became deep red
3 2
P, base, I ). With base already present,
I
2
on heating. Deferred introduction of base provided visible
1
evidence for the postulated origin of chlorides 2b/10b: the
2
red solution obtained on total dissolution of I (1% excess)
lightened to pale orange on addition of imidazole, 2,6-
lutidine, or DBMP but returned to a deep red on either
heating or on addition of Lewis acid. We infer some
1
3
competition by nitrogenous base for I
2
complexation,
1
.
freeing Ph P to form Ph P‚Cl by reaction with chlorinated
3
3
2
Acknowledgment. We thank the Indiana Elks/Purdue
Cancer Center and Proctor and Gamble (T.G.L. fellowships)
and the NIH (CA 60548) for funding, Arlene Rothwell for
MS data, and Phil Fanwick for X-ray analysis.
(
12) Rapid heating (immersion into a preheated bath as in ref 1 and Table
) gave maximal iodide production. Slow heating (25 min to achieve 90
C) of an identical mixture gave a 90% yield of 10a/b (4:1).
1
°
(13) Lemieux, R. U.; Morgan, A. R. Can. J. Chem. 1965, 43, 2190.
14) Garegg, P. J.; Johansson, R.; Samuelsson, B. Synthesis 1984, 168.
(
OL991078R
1818
Org. Lett., Vol. 1, No. 11, 1999