Studies directed toward the total synthesis of azaspiracid. Construction of the C1-C19 carbon backbone and synthesis of the C10, C13 nonnatural transoidal bisspirocyclic ring system

Article abstract of DOI:10.1016/S0040-4039(01)01211-4

The efficient entry to the C₁-C₁₉ carbon backbone of azaspiracid is outlined utilizing a key Julia coupling strategy. Spirocyclization of a C₁₂ sulfone substrate induced formation of the unprecedented, nonnatural transoidal bisspiroketal. Construction of the bisspirocyclic array at C₁₀ and C₁₃, in the absence of the C₁₂ sulfone, led to formation of the cisoidal orientation of the bisspirocycle, with the nonnatural stereochemistry at C₁₃.

Full text of DOI:10.1016/S0040-4039(01)01211-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6035–6039
Studies directed toward the total synthesis of azaspiracid.
Construction of the C1–C19 carbon backbone and synthesis of
the C10, C13 nonnatural transoidal bisspirocyclic ring system†
Rich G. Carter* and David E. Graves
Department of Chemistry and Biochemistry, University of Mississippi, University, MS 38677, USA
Received 19 June 2001; accepted 5 July 2001
Abstract—The efficient entry to the C1–C19 carbon backbone of azaspiracid is outlined utilizing a key Julia coupling strategy.
Spirocyclization of a C12 sulfone substrate induced formation of the unprecedented, nonnatural transoidal bisspiroketal.
Construction of the bisspirocyclic array at C10 and C13, in the absence of the C12 sulfone, led to formation of the cisoidal
orientation of the bisspirocycle, with the nonnatural stereochemistry at C13. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
tions of azaspiracid.1a In this communication, we report
the synthesis of the C1–C19 carbon framework of aza-
spiracid (1) using a sulfone coupling strategy (Scheme
1). In addition, the powerful controlling influence of the
C12 sulfone functionality in the bisspirocyclization is
investigated for the construction of the transoidal5 ori-
entation of the bisspiroketal. Previous work in this
area1b,2b,2c has only disclosed the formation of the
Azaspiracid (1) and its related structures, azaspiracid-2
(2) and azaspiracid-3 (3), have begun to garner signifi-
cant synthetic attention1,2 due to their challenging
spirocyclic structures as well as their considerable toxic-
ity in mice.3,4 Our laboratory has recently disclosed the
construction of the C1–C12, C13–C19 and C21–C25 por-
R1
12
H
10
O
H
1
HO
S
O
13
OH
R2
O
19
21
S
H
O
O
OP
HO
O
H
H
OTBDPS
1 R1 = H, R2 = Me
2 R1 = R2 = Me
3 R1 = R2 = H
26
1
34
OHC
12
O
H
TESO
25
25
O
10
O
H
O
13
35
H
O
19
NH
H
H
47
O
OMe
26
5
O
34
O
O
6
4
N
47
35
H
H
OTBDPS
O
7
OTBDPS
1
1
O
O
13
SO2Ph
H
R
OH
19
O
H
12
OMe
O
12
O
13
H
OMe
H
OMe
19
H
O
O
H
8 R = H
9 R = SO2Ph
10
11
Scheme 1.
* Corresponding author.
†
Dedicated to Professor Alex T. Rowland on the occasion of his retirement.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01211-4

6036
R. G. Carter, D. E. Gra6es / Tetrahedron Letters 42 (2001) 6035–6039
cisoidal5 (10R,13S) stereochemistry in the bisspiro-
cyclization.
mixture of three of the four possible diastereomers.
Conversion of the Julia adduct 16 to the desired keto
sulfone 14 is worthy of further comment. Attempted
oxidation of 16 using Swern conditions7 or Dess–Mar-
tin’s periodinane8 led to a complex mixture of products.
2. Construction of C12,13 linkage
Fortunately, TPAP9 oxidation proved
a feasible
Our initial strategy1a for the construction of the key
C12,13 sigma bond involved an anionic coupling of
sulfone 10 with lactone 11 to yield the keto sulfone 8
directly. Although this strategy did prove modestly
successful, we were discouraged by the disappointing
yields (15–20%) in this transformation (Scheme 2). A
considerable amount of decomposition of the lactone
11 was observed under all reaction conditions. One
potential alternative to 11 was the previously
described1a ester 13. While the ester 13 did provide an
improvement in the production of the required keto
sulfone 14, the yields (up to 40%) continued to fall
short of desirable levels.
method for the synthesis of ketone 14. It should also be
noted that epimerization at C12 of the keto sulfone 14
occurred under the slightly basic media of the TPAP
oxidation to provide an inseparable 1:1 mixture of
sulfone epimers. Subsequent Na/Hg reduction10 of the
keto sulfone 14 yielded the desired ketone 17.
3. Bisspirocyclization
Our approach for the construction of the crucial C10
and C13 spirocyclic linkages invoked a preorganization
strategy by establishing the surrounding ring systems
prior to spirocyclization. It was hoped that these neigh-
boring structural buttresses should provide a favorable
environment for spirocyclization to the desired stereo-
chemical relationships. Treatment of ketone 17 under a
variety of mildly acidic conditions or Lewis acid condi-
tions (e.g. PPTS, PTSA, BF3·Et2O) did induce desilyla-
tion at C17 with in situ cyclization to form the bis-
spiroketal 18 as the only isolable spirocycle (Scheme 4).
A Julia coupling6 strategy with aldehyde 15 might
prove to be a more reliable approach for the formation
of the C12,13 linkage (Scheme 3). The straightforward
conversion of the ester 13 to the aldehyde 15 was
accomplished in 93% overall yield. Subsequent Julia
coupling of aldehyde 15 with sulfone 10 did provide the
desired C12,13 linkage in a gratifying 99% yield, as a
H
OTBDPS
OTBDPS
PhSO2
O
O
13
H
PhSO2
a
OH
+
O
H
O
12
O
12
O
O
13
H
OMe
OMe
H
O
O
10
11
H
8
H
H
OTBDPS
PO
OTBDPS
H
PhSO2
c
PhSO2
OTES
O
+
H
O
O
12
O
12
O
13
OMe
H
OMe
13
O
O
H
MeO2C
12 P = H
13 P = TES
14
10
b
Scheme 2. Reagents and conditions: (a) LDA, THF, −78°C, then 11, 20%; (b) TESOTf, 2,6-lutidine, CH2Cl2, −78°C, 93%; (c)
LDA, THF, −78°C, then 13, −78 to −10°C, 40%.
OTBDPS
OTBDPS
OTBDPS
R
PhSO2
PhSO2
c
d
OTES
OTES
OH
O
H
H
12
O
O
12
O
12
13
13
H
OMe
H
OMe
H
OMe
16
O
O
O
H
O
H
14 R = SO2Ph
17 R = H
10
e
H
H
TESO
H
O
O
13
R
13 R = CO2Me
15 R = CHO
a, b
Scheme 3. Reagents and conditions: (a) DIBAL-H, CH2Cl2, −78°C, 99%; (b) TPAP, NMO, CH2Cl2, mol. sieves, 93%; (c) LDA
(1.15 equiv.), THF; 15 (1.2 equiv.), −78°C, 99%; (d) TPAP, NMO, CH2Cl2, mol. sieves, 81%; e) 5% Na/Hg, THF, MeOH, −10°C,
88%.

R. G. Carter, D. E. Gra6es / Tetrahedron Letters 42 (2001) 6035–6039
6037
OMe
H
O
H
OTBDPS
9
O
OTBDPS
TESO
14
H+ or
10
O
13
O
10
CH2
H
17
13
13
10
O
O
H
O
H
H
H
O
O
O
O
H
Lewis Acid
O
O
H
H
18
17
O
R
R = CH2CH2CH2OTBDPS
Double headed arrows indicate key observed nOe's.
Scheme 4.
The stereochemistry of 18 was established by NOESY
and COSY correlations as the undesired 10R,13S or
cisoidal5 stereochemistry. These results1b are in good
agreement with Dounay and Forsyth2b,2c who indepen-
dently observed a similar preference for the 10R,13S
stereoisomer. In addition, our own high level ab initio
calculations [HF/6-31G(d) and B3LYP/6-31G(d)ꢀꢀHF/6-
31G(d)] show that the cisoidal isomer 18 is up to 7
kcal/mol more stable. Based on the experimental and
theoretical data, an alternate strategy for the construc-
tion of the transoidal bisspirocycle was required.
cisoidal (10R,13R)13 bisspirocycle 20a and 20b, respec-
tively, as single epimers. These structures were once
again assigned via NOESY and COSY 2D NMR exper-
iments. In order to correlate the bisspirocycle 20 to the
previously described cisoidal (10R,13S) bisspirocycle
18, the C12 sulfone function was removed under Na/Hg
conditions to provide 18 in an unoptimized 60% yield.
It should also be noted that submission of keto sulfone
14, as the 1:1 mixture at C12, to the identical acidic
conditions (CSA, MeCN) resulted in the formation of
the cisoidal bisspirocycle 20 as a 1:1 mixture at C12
(72% yield).
One potential option lies in the immediate precursor to
the ketone 17: keto sulfone 14. The steric bulk imparted
by the C12 sulfone moiety should have a dramatic
impact on the reactivity of any oxonium ion derived
from 14.11 As stated previously, the keto sulfone 14
exists as a 1:1 inseparable mixture at C12. Fortunately,
removal of the C17 TES protecting group under
buffered TBAF conditions12 did provide a separable 1:1
ratio of the R and S stereoisomers at C12 (Scheme 5).
Treatment of the separated compounds 19a and 19b
under acidic conditions (CSA, MeCN) produced the
As considerable solvent effects have been observed in
bisspirocyclizations,14 it was hoped that treatment of
keto sulfone 14 or 19 under alternate acidic conditions
(e.g. PPTS, BF3·Et2O, CSA) in a variety of solvents
(e.g. t-BuOH, CH2Cl2, PhH) would provide access to
the transoidal orientation of the bisspiroketal. Only
camphorsulfonic acid (CSA) in benzene led to the
formation of a new bisspirocycle as a minor product
(:5–10%), which was identified as the nonnatural
R'
R
R
SO2Ph
R'
OTBDPS
OTBDPS
OTBDPS
TESO
HO
12
12
12
10
H
H
a
17
b
O
13
O
O
O
10
O
O
H
O
H
H
O
H
O
O
O
O
O
O
H
H
H
H
19α R = H, R' = SO2Ph
19β R = SO2Ph, R' = H
20α R = H, R' = SO2Ph
20β R = SO2Ph, R' = H
14
O
OMe
H
OMe
H
H
H
SO2Ph
SO2Ph
OTBDPS
OTBDPS
O
H
O
O
H
O
S
H
H
H
H
12
O2S
12
O
O
13
H
O
10
13
O
13
10
O
H
H
13
10
H
H
H
O
CH2
CH2
H
H
O
O
10
O
O
H
O
H
O
H
H
O
H
O
H
H
H
O
20α
O
20β
R
R
R = CH2CH2CH2OTBDPS
Double headed arrows indicate key observed nOe's.
Scheme 5. Reagents and conditions: (a) TBAF, HOAc, THF, 75%; (b) CSA, MeCN, 82% for 20a, 60% for 20b.

6038
R. G. Carter, D. E. Gra6es / Tetrahedron Letters 42 (2001) 6035–6039
SO2Ph
SO2Ph
H
SO2Ph
OTBDPS
OTBDPS
OTBDPS
H
12
12
10
O
12
O
10
O
H
10
O
a
b
H OH
13
H
13
O
O
+ 20
O
H
H
H
H
14
O
O
O
19
O
H
H
19
O
O
H
R
20
22
21
O
Me
H
O
H
O
O
11
SO2Ph
OTBDPS
H
H
H
17
6
O
10
O
O
H
H
SO2
H
13
H
O
O
H
H
O
O
Me
H
H
22
R = CH2CH2CH2OTBDPS
Double headed arrows indicate key observed nOe's.
Scheme 6. Reagents and conditions: (a) n-BuLi, THF, −78°C, 83%; (b) CSA, PhMe 43% of 22, 49% of 20.
transoidal5 (10S,13R) bisspirocycle 22. All other
attempted conditions continued, however, to provide
the cisoidal (10R,13R) spirocycle as the predominate
product. In order to access an alternate bisspirocycliza-
tion precursor, the sulfone 20 was treated with n-BuLi
at −78°C, which coaxed b-elimination to yield the elab-
orate enol ether 21 (Scheme 6). It was imperative that
this reaction be quenched at −78°C. If the reaction was
allowed to warm to −10°C, the alkoxide readded to the
C13 alkene to provide the sulfone 20. Next, spirocycliza-
tion of the alcohol 21 under acidic conditions in toluene
induced formation of the nonnatural transoidal spiro-
cycle 22, with the 10S,12R,13R stereochemistry, along
with nearly equal amounts (4:5) of the cisoidal
(10R,13R) spiroketal 20 in an overall 92% yield.15
While the spirocycle 22 was isolated as a single isomer
at C12, the epimeric ratio at C12 in the previously
observed spiroketal 20 was approximately 3:1 favoring
the 12R or a sulfone. The stereochemistry of 22 was
established via COSY and ROESY correlations, with
key observed NOEs between the C6 ether and the C11
hydrogens as well as the C9 alkene and the C17 hydro-
gens (Scheme 6). The stereochemical arrangement of 22
at C10 places the spirocyclic oxygen in a pseudoequato-
rial orientation in the half chair of the pyran ring. The
transoidal spirocycle 22 appears to be the result of
kinetic control under the described reaction conditions.
While resubmission of the spirocycle 20 to acidic condi-
tions (CSA, PhMe, 18 h) did not result in the formation
of any of the transoidal (10S,13R) product 22, treat-
ment of transoidal spirocycle 22 to the identical condi-
tions (CSA, PhMe) did lead to slow conversion toward
the cisoidal product 20 with extended reaction times
4. Conclusion
The first successful example of the construction of the
unprecedented transoidal (10S,13R) bisspirocycle in the
azaspiracid ring system has been achieved. The synthe-
sis of the transoidal bisspirocycle is facilitated by the
novel use of a sulfone located in the C12 position. The
apparent preference for the 10S,13R13 transoidal orien-
tation, as shown in 22, over the alternate transoidal
stereochemistry in the natural product 1, may be worth
further consideration. Construction of the C10 and C13
spirocyclic linkages in the absence of the C12 sulfone
resulted in formation of the undesired cisoidal
(10R,13S) stereochemistry. Finally, the efficient entry
into the C1–C19 carbon backbone of azaspiracid (1) has
been achieved using a key Julia coupling strategy. Our
progress toward the natural stereochemistry at C10 and
C13 as well as the total synthesis of azaspiracid will be
reported in due course.
Acknowledgements
The authors thank the University of Mississippi for
their generous support of this work, Dr. Todd D.
Williams (University of Kansas) for mass spectral data,
Dr. Steven R. Davis for molecular modeling calcula-
tions, Dr. Roger Hanselmann (DuPont Pharmaceuti-
cals), T. Campbell Bourland and David J. Weldon for
their helpful discussions.
1
(40% conversion to 20a by H NMR after 24 h).16 The
References
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.