A modular, stereoselective approach to spiroketal synthesis

Article abstract of DOI:10.1055/s-0031-1290670

A highly convergent and flexible synthetic approach to stereochemically defined spiroketals is reported. Substituents can be incorporated at various positions around the spiroketal framework without significant disruption to the synthetic scheme. The approach has been exploited to prepare the spiroketal fragment of milbemycin β Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290670

LETTER
▌1489
lAetteMr odular, Stereoselective Approach to Spiroketal Synthesis
Stereoselective Approach to Spiroketal Synthesis
Michael T. Crimmins,* Adam M. Azman1
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Fax +1(919)9665177; E-mail: crimmins@email.unc.edu
Received: 10.02.2012; Accepted after revision: 30.03.2012
considerable value to synthetic and medicinal chemists. A
modular approach to the synthesis of spiroketals with sig-
nificant versatility and minimal operational complexity
for substituent interchange is reported here.
Abstract: A highly convergent and flexible synthetic approach to
stereochemically defined spiroketals is reported. Substituents can
be incorporated at various positions around the spiroketal frame-
work without significant disruption to the synthetic scheme. The ap-
proach has been exploited to prepare the spiroketal fragment of
milbemycin β14.
The general retrosynthetic approach is illustrated in
Scheme 1. Spiroketal 1 would arise from pseudo-C2-sym-
metrical dihydroxyketone 2. Hydroxyketone 2 would be
bisected to give A-ring chiral aldehyde 3 and B-ring β-
ketophosphonate 4. The relative and absolute stereochem-
istry of each fragment would be readily accessible from
diastereoslective N-acylthiazolidinethione aldol addition
methodology.7,8 The bisection of the dihydroxyketone to
the chiral aldehyde and chiral β-ketophosphonate is note-
worthy, since the convergent, modular nature of the syn-
thesis was an essential component of this approach. By
disconnecting as shown, the functionality of the A- and B-
rings can be independently changed obviating the need to
repeat the entire synthesis. Only the shorter synthesis of
one chiral fragment is required. In this manner, ‘aldehyde’
and ‘phosphonate’ fragments can be mixed and matched
with ease to create a variety of novel spiroketals.
Key words: spiroketals, asymmetric aldol addition, milbemycin
The spiroketal is a substructure that is commonly found in
natural products.2 Spiroketal-containing natural products
range from elegantly simplistic pheromones3 to complex
polyketides4 and marine toxins.5 The spiroketal frame-
work is a rigid structure owing to stabilization by the
unique stereoelectronic phenomenon known as the ano-
meric effect.6
Due to the frequent occurance of spiroketals in biological-
ly active natural products, and the potential of spiroketals
as privileged structures in medicinal chemistry, a general
strategy for the construction of spiroketals with substitu-
ents strategically and interchangeably positioned in vari-
ous locations around the structural framework would hold
Me
3
2
OH
O
OH
A
O
3
9
8
spiroketalization
O
B
Me
Me
Br
8
9
2
Me
Br
HWE olefination–
1,4-reduction
1
TES
O
O
OTES
O
O
(EtO)2P
9
+
8
3
2
H
Me
Me
Br
3
4
A-ring aldehyde
B-ring β-ketophosphonate
aldol
H
aldol
O
O
8
H
2
Br
5
6
Scheme 1 Retrosynthesis of spiroketal 1
SYNLETT 2012, 23, 1489–1492
Advanced online publication: 29.05.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290670; Art ID: ST-2012-S0120-L
© Georg Thieme Verlag Stuttgart · New York

1490
M. T. Crimmins, A. M. Azman
LETTER
TiCl4
(–)-sparteine
NMP
1) TESOTf
2,6-lutidine
CH2Cl2
S
S
O
OH
O
S
N
S
N
OHC
2) i-Bu2AlH
CH2Cl2
89% (2 steps)
Me
Me
Br
Bn
Bn
Br
8
7
6
CH2Cl2
87%, 16:1 dr
O
OTES
O
OTES
1) Ph3P=CHCO2Et
THF, 92%
EtO
H
2) TsNHNH2, NaOAc
DME–H2O, 89%
Me
Me
Br
Br
9
10
O
O
OTES
(MeO)2P(O)CH3
(MeO)2P
n-BuLi, THF
Me
B-ring β-ketophosphonate
98%
Br
4
Scheme 2 Synthesis of phosphonate 4
The first spiroketal 1 targeted incorporated an A-ring ter- tion in 98% yield to give B-ring β-ketophosphonate 4 in
minal alkene and a B-ring aryl bromide in the 2- and 8-po- six steps and 62% overall yield.
sitions of the spiroketal, respectively. The synthesis of the
The A-ring aldehyde fragment was also prepared through
B-ring β-ketophosphonate fragment commenced with a
thiazolidinethione-mediated ‘Evans syn’-aldol addition7a
thiazolidinethione-mediated ‘Evans syn’-aldol addition7a
with 3-butenal10 (5) to give aldol adduct 11 in 92% yield
with p-bromobenzaldehyde (6) to yield aldol adduct 8 in
and 20:1 diastereomeric ratio (Scheme 3). Alcohol protec-
87% isolated yield of the major diastereomer and a 16:1
tion directly followed by chiral auxiliary reduction pro-
diastereomeric ratio overall (Scheme 2). Protection of the
vided A-ring aldehyde fragment 3 in three steps and 56%
secondary alcohol followed by reductive removal of the
overall yield.
chiral auxiliary yielded aldehyde 9 in 89% yield over two
The two fragments were coupled in a Horner–
Wadsworth–Emmons olefination utilizing barium
hydroxide11 as mild base to provide the α,β-unsaturated
ketone in 83% yield. Selective reduction of the α,β-unsat-
steps. Wittig olefination followed by diimide reduction9
provided ethyl ester 10. Completion of the B-ring β-keto-
phosphonate was achieved through a Claisen condensa-
1) TESOTf
2,6-lutidine
CH2Cl2, 83%
S
TiCl4
(–)-sparteine
NMP
O
S
O
OH
S
N
S
N
2) i-Bu2AlH, CH2Cl2
73%
Me
O
Me
11
Bn
Bn
H
7
5
CH2Cl2
92%, 20:1 dr
O
OTES
1) 4, Ba(OH)2
THF, 83%
OTES
Me
O
OTES
H
2) i-Bu2AlH,
Me
Me
3
CuMe (cat.)
HMPA, THF
91%
Br
12
A-ring aldehyde
Me
3
2
1) TBAF, THF
100%
H
A
B
O
O
8
2) PPTS, CH2Cl2
86%
NOE
signal
9
H
Me
Br
1
Scheme 3 Synthesis of spiroketal 1
Synlett 2012, 23, 1489–1492
© Georg Thieme Verlag Stuttgart · New York

LETTER
Stereoselective Approach to Spiroketal Synthesis
1491
urated ketone in the presence of the terminal olefin was
accomplished using diisobutylaluminum hydride with
HMPA and catalytic methyl copper as an additive, form-
ing saturated ketone 12 in 91% yield without over reduc-
tion.12
TiCl4
(–)-sparteine
S
S
O
O
OH
R
NMP
S
N
S
N
O
H
R
Bn
13
Bn
CH2Cl2
To access the desired spiroketal, the triethylsilyl ether
protective groups were removed with TBAF in quantita-
tive yield, providing the open-chain dihydroxyketone. Im-
mediate treatment with a catalytic amount of PPTS
converted the dihydroxyketone into desired spiroketal 1 in
86% yield as a single diastereomer. The spiroketal was
prepared in ten longest linear steps and provided gram
quantities of the desired spiroketal in 40% overall yield.
Relative stereochemistry was ultimately determined
through 2-D NOESY analysis (see Supporting Informa-
tion).
14 (R = Me)
15 (R = i-Pr)
14 54%, 10:1 dr
15 69%, >20:1 dr
O
OTES
1) TESOTf, 2,6-lutidine
CH2Cl2
1) 4, Ba(OH)2, THF
H
R
2) i-Bu2AlH, CuMe (cat.)
2) i-Bu2AlH, CH2Cl2
HMPA, THF
16 84% (2 steps)
17 64% (2 steps)
18 66% (2 steps)
19 76% (2 steps)
16 (R = Me)
17 (R = i-Pr)
A-ring aldehydes
Two further spiroketals were targeted (20 and 21) with a
B-ring aryl bromide identical to 1, and a modified A-ring
architecture. The terminal alkene was shifted to the 3-po-
sition and either a methyl group (20) or isopropyl group
(21) was located in the 2-position. Demonstrating the
modular approach to spiroketal synthesis, only the A-ring
aldehyde fragment needed to be prepared in each case, as
the B-ring β-ketophosphonate needed (4) is the same as
previously prepared.
3
R
OTES
O
OTES
2
A
HF
O
R
6
THF, H2O
Br 20 81%
21 48%
O
Me
*
B
8
9
18 (R = Me)
19 (R = i-Pr)
Me
Br
20 (6S, R = Me)
21 (6R, R = i-Pr)
Scheme 4 Synthesis of spiroketals 20 and 21
Thiazolidinethione-mediated ‘Evans syn’-aldol addition7a
with known thiazolidinethione 137 and either acetalde-
hyde or isobutyraldehyde gave aldol adducts 14 and 15 in
54% yield (10:1 dr) and 69% yield (>20:1 dr), respective-
ly (Scheme 4). Alcohol protection followed by reduction
of the auxiliary completed the new A-ring aldehyde frag-
ments 16 and 17 in a three-step overall yield of 45% and
47%, respectively.
rosynthetically, milbemycin β14 could be derived from
key spiroketal 23 (Scheme 5). Spiroketal 23 can readily be
constructed utilizing this modular approach through prep-
aration of B-ring β-ketophosphonate 25 and A-ring alde-
hyde 24.
Me
Me
Horner–Wadsworth–Emmons coupling11 of previously
prepared B-ring β-ketophosphonate 4 and A-ring alde-
hydes 16 or 17, followed by selective 1,4-reduction,12 re-
sulted in 66% and 76% yields of ketones 18 and 19,
respectively. One-pot HF-promoted deprotection–cycli-
zation of ketone 18 proceeded in 81% yield to give spiro-
ketal 20. Based on extensive 1D and 2D NMR analysis,
spiroketal 20 was formed in a 13:1 dr favoring the singly
anomeric 6S diastereomer at the C6 spiroketal carbon at-
om. The analogous deprotection of ketone 19 yielded spi-
roketal 21 in 48% yield. A single diastereomer favoring
the doubly anomeric 6R diastereomer at the C6 spiroketal
carbon atom was formed, as determined by extensive 1D
and 2D NMR analysis. Both spiroketal 20 and 21 were
prepared in nine longest linear steps and overall yields of
34% and 23%, respectively.
O
O
Me
3
Me
O
A
O
B
2
Me
8
Me
O
O
10
OH
23
OH
Me
OH
22
milbemycin β14
TBS
TMS
O
O
O
O
O
OTBS
+
3
(MeO)2P
8
2
10
H
Me
Me
24
25
B-ring β-ketophosphonate
A-ring aldehyde
This modular approach to spiroketal synthesis has also
been incorporated into natural product synthesis. We have
previously reported the total synthesis of spirofungins A
and B13 incorporating this versatile spiroketal synthesis.
Scheme 5 Milbemycin β14 partial retrosynthesis
The B-ring β-ketophosphonate fragment was prepared
through an iterative thiazolidinethione-mediated acetate
aldol addition7b developed in our laboratory. Addition of
3-butenal (5)10 to a solution of the chlorotitanium enolate
of N-acetylthiazolidinethione (R)-26 produced the aldol
Our recent attention was turned to milbemycin β14 (22) as
a possible target. Milbemycin β14 is an acaricidal and ne-
matocidal macrolactone isolated from the fermentation
broth of a strain of Streptomyces bingchenggensis.14 Ret-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1489–1492

1492
M. T. Crimmins, A. M. Azman
LETTER
adduct 27 in 80% yield and greater than 20:1 diastereo- In conclusion, we have demonstrated a versatile, modular
meric ratio (Scheme 6). Protection of the secondary alco- synthesis of stereochemically defined spiroketals where
hol followed by reductive cleavage of the chiral auxiliary individual rings can be mixed and matched. Spiroketal
provided aldehyde 28 in 66% yield over two steps. The substituents can be easily translated to various positions
second acetate aldol addition7b with thiazolidinethione without disrupting the overall synthetic approach. The
(S)-26 provided iterative aldol adduct 29 in 88% yield as modular approach to spiroketals can be applied toward the
a single stereoisomer. Protection of the C10 secondary al- total synthesis of spiroketal-containing natural products.
cohol as its TMS ether and direct displacement of the aux-
iliary with lithiated dimethyl methyl phosphonate
provided B-ring β-ketophosphonate 25 in 83% yield over
Acknowledgment
Financial support from the National Institute of General Medical
Sciences (GM60567) is gratefully acknowledged.
two steps. The B-ring phosphonate fragment was synthe-
sized in six steps and 39% overall yield.
1) TBSOTf
2,6-lutidine
CH2Cl2
Supporting Information for this article is available online at
S
S
O
TiCl4
i-Pr2NEt
O
OH
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
S
N
Me
S
N
2) i-Bu2AlH
CH2Cl2
66% (2 steps)
O
References
Mes
(R)-26
Mes
27
H
5
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CH2Cl2
80%, >20:1 dr
S
S
O
O
OH OTBS
O
OTBS
TiCl4
i-Pr2NEt
S
N
Me
+
S
N
H
CH2Cl2
88%
Mes
(S)-26
Mes
O
28
29
TMS
OTBS
1) TMSCl, NEt3
DMAP, CH2Cl2
O
O
(MeO)2P
10
8
2) (MeO)2P(O)CH3
n-BuLi, THF
83% (2 steps)
25
B-ring β-ketophosphonate
Scheme 6 Synthesis of β-ketophosphonate 25
Horner–Wadsworth–Emmons coupling11 of B-ring β-
ketophosphonate 25 with known protected A-ring alde-
hyde 2415 provided unsaturated ketone 30 in 88% yield.
Selective 1,4-reduction12 of the enone followed by one-
pot tris-silyl ether deprotection–cyclization yielded spiro-
ketal 23 as a single isomer in 84% yield over two steps.
Spiroketal 23 was completed in nine overall steps (longest
linear sequence) and 29% overall yield (Scheme 7). The
relative configuration of the spiroketal was confirmed
through 2D NOESY analysis.
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TMS
OTBS
TBS
OTBS
Me
O
O
O
O
25, Ba(OH)2
3
10
8
2
H
THF, H2O
88%
Me
Me
Me
24
30
A-ring aldehyde
Me
3
1) i-Bu2AlH,
CuMe (cat.)
HMPA, THF
A
O
B
8
2
Me
H
O
H
10
H
2) HF–py, PhMe
82% (2 steps)
OH
NOE
signals
23
Scheme 7 Synthesis of spiroketal 23
Synlett 2012, 23, 1489–1492
© Georg Thieme Verlag Stuttgart · New York

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