Synthetic studies on azaspiracid: Synthesis of key intermediate for the construction of the FGHI ring system

Article abstract of DOI:10.1055/s-2007-985585

A highly stereoselective and convergent approach for the key intermediate of the FGHI ring system of azaspiracid is described. The synthesis features the desymmetrization strategy for the construction of the C27-C33 fragment, Masamune-Roush coupling condi

Full text of DOI:10.1055/s-2007-985585

2262
LETTER
Synthetic Studies on Azaspiracid: Synthesis of Key Intermediate for the
Construction of the FGHI Ring System
Synthetic
.Studies on A
S
zaspiracid . Yadav,* C. Venugopal
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: yadavpub@iict.res.in
Received 4 June 2007
molecular assembly and fascinating biological activity of
Abstract: A highly stereoselective and convergent approach for
the key intermediate of the FGHI ring system of azaspiracid is
described. The synthesis features the desymmetrization strategy for
the construction of the C27–C33 fragment, Masamune–Roush cou-
these natural toxins have attracted considerable interest
among synthetic chemists.6 All the azaspiracids (AZA1–
AZA11) have similarity in the C27–C40 domain. The
pling conditions for the C33–C34 bond formation, and Sharpless synthesis of the C26–C40 fragment has been reported by
the Nicolaou,6f,l,t,6w–y Forsyth,6b,c,h,z and Sasaki groups.6n
asymmetric dihydroxylation as the key steps. One more important
feature of this synthetic route is that we can synthesize other
Still there is a scope for the efficient synthetic strategies
enantiomers of the FGHI ring system by changing asymmetric
and approaches to address the complex natural product.
hydroboration conditions and valerolactone.
Our ongoing research on the synthesis of biologically
Key words: desymmetrization, Masamune–Roush coupling condi-
active molecules by desymmetrization strategy, and the
azaspiro system encouraged us to synthesize the C27–C40
fragment of the proposed azaspiracid 1. Our synthesis
features desymmetrization strategy, Masamune–Roush
coupling conditions,7 and Sharpless asymmetric dihy-
droxylation.8
tions, Sharpless asymmetric dihydroxylation, asymmetric hydro-
boration
The azaspiracids are the causative agents of human
poisonings associated with the consumption of shellfish
that were first recognized in the Netherlands in 1995.1
Yasumoto and co-workers isolated AZA1 from the
mussel Mitilus edulis from Killary Harbor, Ireland and
reported its structure (Figure 1).2 The structure proposed
by Yasumoto and co-workers was revised and established
by a total synthesis by Nicolaou and co-workers.3 Up to
now five azapiracids (AZA1–AZA5) have been isolated
and their structures have been elucidated by extensive
NMR studies and FABMS–MS experiments.4 The other
azapiracids (AZA6–AZA11) have been detected using a
combination of liquid chromatography and multi-tandem
mass spectrometry (LC–MSn).5 The unusual complex
The retrosynthetic analysis is based on a convergent ap-
proach as outlined in Scheme 1. We envisioned the attach-
ment of the C26 aldehyde 4 to the C27 acetylene 3, and
double intramolecular hetero-Michael addition6e,h,z reac-
tion for the FG ring formation. The C27 acetylene would
be obtained by sequential formation of the H and I rings
from the acetylene 5, which in turn could be obtained
from coupling of aldehyde 6 and ketophosphonate 7. The
aldehyde 6 could be obtained from the desymmetrization
strategy and the ketophosphonate 7 could be obtained
from (R)-valerolactone.
Figure 1 Proposed and revised structures of azaspiracid. R1 = H, Me; R2 = H, Me; R3 = H, OH; R4 = H, OH.
SYNLETT 2007, No. 14, pp 2262–2266
0
3
.0
9
.2
0
0
7
Advanced online publication: 14.08.2007
DOI: 10.1055/s-2007-985585; Art ID: D17007ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthetic Studies on Azaspiracid
2263
Scheme 1 Retrosynthetic analysis.
The synthesis of aldehyde 6 began with the precursor 8, pound 16. Deprotection of THP ether followed by IBX
which was prepared earlier in our lab by desymmetriza- oxidation gave the aldehyde 17. Treatment of the alde-
tion strategy and utilized in the synthesis of rifamycin, hyde with lithium anion of methyldimethylphosphonate
fragments of (+)-discodermolide, fragment of scytophy- provided b-hydroxyphosphonate, which was subjected to
cin C, prelactone-B, (+)-membrenone-C and its 7-epimer, oxidation with Dess–Martin periodinane to afford b-keto-
crocacin-C.9 Compound 8 was converted into 9 as de- phosphonate 712 (Scheme 3).
tailed earlier; further deprotection of the benzyl group by
Aldehyde 6 and ketophosphonate 7 were coupled using
Li in liquid ammonia provided a diol, which was selec-
Masamune–Roush coupling conditions7 to afford enone
tively protected with TBDPS-Cl to obtain 10. The second-
18,13 which was subjected to Sharpless asymmetric
ary hydroxyl group was converted into the xanthate ester
dihydroxylation8 with AD-mix a to give a 95:5 diastereo-
and reduced with n-Bu3SnH to give the compound 11.
Deprotection of acetonide and treatment with para-meth-
oxybenzaldehyde dimethyl acetal yielded the compound
12. Treatment of 12 with DIBAL-H yielded the mono pro-
tected diol, which on oxidation with 2-iodoxybenzoic acid
(IBX) afforded the aldehyde 6 (Scheme 2).
meric mixture of diols (92% yield), and further protected
as its acetonide 19.14 The stereoselective reduction of the
keto functionality of 19 using various reagents afforded
the undesired R isomer predominantly. With K-selectride,
the R isomer was obtained exclusively, and the newly
formed stereogenic center was conformed by NMR stud-
The synthesis of ketophosphonate 7 started with 3-meth- ies of its (R)- and (S)-MPA esters. We then decided to in-
ylglutaric acid. Resolution of 3-methylglutaric acid vert the stereochemistry of the carbinol carbon after the
monomethyl ester with cinchonidine followed by reduc- formation of the spirocycle. The hydroxyl group was pro-
tion of acid, and lactonization afforded 14.10 Dichloro ole- tected as its benzyl ether 20.15 Deprotection of the TBDPS
fination of lactone 14 with CCl4 and triphenylphosphine ether and TMS groups by using TBAF, followed by con-
(TPP) followed by reductive opening of the resulting enol version of the resulting hydroxyl group into the azide via
ether with Li sand gave the alkyne 15.11 The hydroxyl methanesulfonate and deprotection of the acetonide with
group of the alkyne was protected as its THP ether and the CSA afforded the corresponding diol. Protecting the diol
alkyne was treated with TMS chloride to furnish com- as its diTBDMS ether using TBSOTf gave 21,16 which on
O
OH
O
O
OBn
O
O
c, d
a, b
Ref. 9
TBDPSO
HO
OBn
10
9
8
PMP
O
O
OPMB
O
O
g, h
CHO
e, f
TBDPSO
TBDPSO
TBDPSO
12
11
6
Scheme 2 Reagents and conditions: (a) Li, liquid NH3, THF, –78 °C; (b) TBDPS-Cl, imidazole, CH2Cl2, 0 °C to r.t., 95% (two steps); (c)
CS2, NaH, MeI, THF, 0 °C to r.t.; (d) n-Bu3SnH, AIBN, toluene, 100 °C, 90% (two steps); (e) PPTS, MeOH, r.t.; (f) p-MeOC6H4CH(OMe)2,
cat. PPTS, CH2Cl2, 0 °C–r.t., 81% (two steps); (g) DIBAL-H, CH2Cl2, –78 °C; (h) IBX, DMSO, CH2Cl2, r.t., 92% (two steps).
Synlett 2007, No. 14, 2262–2266 © Thieme Stuttgart · New York

2264
J. S. Yadav, C. Venugopal
LETTER
Me
Me
Me
c, d
a, b
ref. 10
HOOC
COOH
HO
O
O
13
15
14
Me
SiMe3
O
O
Me
SiMe3
Me
SiMe3
g, h
e, f
MeO
MeO
P
OHC
THPO
16
17
7
Scheme 3 Reagents and conditions: (a) TPP, CCl4, THF, reflux; (b) Li sand, THF, reflux, 85% (two steps); (c) 2,3-dihydropyran (DHP), cat.
PPTS, CH2Cl2, 0 °C–r.t.; (d) TMS-Cl, n-BuLi, THF, –78 °C, 88% (two steps); (e) PPTS, MeOH, 0 °C–r.t.; (f) IBX, DMSO, CH2Cl2, r.t., 93%
(two steps); (g) n-BuLi–MeP(O)(OMe)2, –78 °C; (h) Dess–Martin periodinane, NaHCO3, 0 °C–r.t., 81% (two steps).
SiMe3
OPMB
O
b, c
a
6
+
7
TBDPSO
18
OPMB
OBn
OPMB
SiMe3
O
SiMe3
O
O
d, e
TBDPSO
TBDPSO
O
O
20
19
OPMB
OTBS
OBn
OBn
O
OH
f– j
n
k–m
N3
5
N3
OTBS
OH
21
22
Scheme 4 Reagents and conditions: (a) i-Pr2NEt, LiCl, MeCN, r.t., 96%; (b) AD-mix a, MeSO2NH2, NaHCO3, t-BuOH–H2O (1:1), 0 °C,
92%; (c) 2,2-DMP, cat. PPTS, CH2Cl2, 0 °C–r.t., 95%; (d) K-selectride, THF, –78 °C; (e) NaHMDS, BnBr, THF–DMF (2:1), 0 °C, 81% (two
steps); (f) TBAF, THF, 0 °C to r.t.; (g) MeSO2Cl, Et3N, CH2Cl2, 0 °C; (h) NaN3, DMF, 90 °C, 93% (three steps); (i) CSA, MeOH, 0 °C to r.t.;
(j) TBSOTf, 2,6-lutidine, 0 °C, 81% (two steps); (k) DDQ, CH2Cl2–H2O (19:1), 0 & deg;C; (l) Dess–Martin periodinane, NaHCO3, CH2Cl2,
0 °C to r.t.; (m) TBAF–AcOH (5:1), THF, 0 °C to r.t., 87% (three steps); (n) cat. PPTS, MeOH, r.t., quant.
treatment with DDQ led to PMB deprotection to furnish References and Notes
the alcohol which on oxidation using Dess–Martin
reagent gave the corresponding ketone. Deprotection
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gave 22.17 This was then subjected to ketal formation by
PPTS in methanol yielding a 1:4 mixture of isomers 518
(Scheme 4).
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In conclusion, we have developed a highly convergent
synthetic route towards the FGHI ring domain of aza-
spiracids (AZA1–AZA11). All the stereogenic centers
were obtained through desymmetrization strategy (which
our group has utilized to synthesize a number of natural
products), Sharpless asymmetric dihydroxylation, and
Masamune–Roush coupling conditions yielding exclu-
sively the E olefin. Further studies towards the total syn-
thesis of azaspiracids are currently underway and will be
reported in due course.
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Acknowledgment
C.V. thanks CSIR New Delhi for a research fellowship.
Synlett 2007, No. 14, 2262–2266 © Thieme Stuttgart · New York

LETTER
J.; Aiguade, J. Angew. Chem. Int. Ed. 2001, 40, 3663.
Synthetic Studies on Azaspiracid
(13) Analytical Data for Compound 18:
2265
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Liquid; [a]D25 –20.18 (c = 2.0, CHCl3). IR (Neat): 2958,
2172, 1671, 1613, 1513, 1462, 1427, 1249, 1172, 1110,
1036, 843 cm–1. 1H NMR (300 MHz, CDCl3): d = 0.13 (s, 9
H), 0.85 (d, J = 6.7 Hz, 3 H), 0.89 (m, 1 H), 0.94 (d, J = 6.6
Hz, 3 H), 0.98 (d, J = 6.2 Hz, 3 H), 1.04 (s, 9 H), 1.49–1.61
(m, 1 H), 1.64–1.78 (m, 2 H), 2.14–2.45 (m, 6 H), 2.55–2.65
(m, 1 H), 3.25–3.32 (m, 1 H), 3.37 (dd, J = 6.4, 9.8 Hz, 1 H),
3.45–3.52 (m, 1 H), 3.76 (s, 3 H), 4.33 (q, J = 11.3, 16.6 Hz,
2 H), 6.06 (d, J = 15.8 Hz, 1 H), 6.66–6.78 (m, 1 H), 6.75 (d,
J = 8.6 Hz, 2 H), 7.09 (d, J = 8.6 Hz, 2 H), 7.29–7.42 (m, 6
H), 7.59–7.65 (m, 4 H). 13C NMR (100 MHz, CDCl3): d =
0.1, 15.6, 18.1, 19.2, 19.5, 26.8, 26.9, 28.8, 33.3, 33.5, 34.5,
36.4, 45.6, 55.1, 68.7, 71.6, 81.2, 86.2, 105.2, 113.6, 127.5,
129.2, 129.5, 130.5, 132.1, 133.8, 135.5, 144.7, 159.0,
199.4. HRMS (ESI): m/z [M + NH4]+ calcd for C44H62O4Si2:
728.4530; found: 728.4501.
(14) Analytical Data for Compound 19:
Liquid; [a]D25 –2.584 (c = 0.6, CHCl3). IR (Neat): 2958,
2931, 2172, 1714, 1610, 1513, 1462, 1374, 1301, 1249,
1169, 1082, 1034, 844, 758, 703, cm–1. 1H NMR (300 MHz,
CDCl3): d = 0.12 (s, 9 H), 0.85 (d, J = 6.7 Hz, 3 H), 0.97 (d,
J = 4.5 Hz, 6 H), 1.05 (s, 9 H), 1.30–1.39 (m, 1 H), 1.36 (s,
3 H), 1.40 (s, 3 H), 1.48–1.62 (m, 2 H), 1.68–1.90 (m, 3 H),
2.12–2.27 (m, 3 H), 2.35 (dd, J = 6.0, 18.1 Hz, 1 H), 2.74 (dd,
J = 6.0, 18.1 Hz, 1 H), 3.29–3.47 (m, 2 H), 3.48–3.58 (m, 1
H), 3.76 (s, 3 H), 3.85 (d, J = 7.5 Hz, 1 H), 3.96–4.10 (m, 1
H), 4.24 (d, J = 11.3 Hz, 1 H), 4.37 (d, J = 11.3 Hz, 1 H), 6.74
(d, J = 9.0 Hz, 2 H), 7.08 (d, J = 8.3 Hz, 2 H), 7.64 (m, 6 H),
7.60–7.68 (d, J = 6.7 Hz, 4 H). 13C NMR (100 MHz, CDCl3):
d = 0.1, 15.8, 18.4, 19.2, 19.4, 26.2, 26.6, 26.8, 27.3, 33.2,
33.4, 35.3, 35.8, 44.0, 55.2, 68.7, 71.7, 75.3, 79.6, 85.5, 86.2,
105.1, 109.9, 113.6, 127.5, 129.1, 129.4, 131.0, 133.9,
135.6, 158.9, 208.9. HRMS (ESI): m/z [M + Na]+ calcd for
C47H68O6Si2: 807.4452; found: 807.4474.
(15) Analytical Data for Compound 20:
Viscous liquid; [a]D25 –21.804 (c = 0.6, CHCl3). IR (KBr):
794, 1071, 1248, 1513, 2172, 2958 cm–1. 1H NMR (300
MHz, CDCl3): d = 0.12 (s, 9 H), 0.78–0.86 (d, J = 6.7 Hz, 3
H), 0.87–0.93 (d, J = 6.7 Hz, 3 H), 0.94–1.00 (d, J = 6.0 Hz,
3 H), 1.04 (s, 10 H), 1.21–1.39 (m, 1 H), 1.33 (s, 3 H), 1.35
(s, 3 H), 1.40–1.88 (m, 7 H), 1.99–2.10 (dd, J = 6.7, 16.6 Hz,
1 H), 2.12–2.22 (dd, J = 5.2, 16.6 Hz, 1 H), 3.31–3.40 (dd,
J = 6.7, 9.8 Hz, 1 H), 3.42–3.56 (m, 3 H), 3.58–3.65 (dd, J =
3.7, 8.3 Hz, 1 H), 3.73 (s, 3 H), 4.01–4.14 (m, 1 H), 4.24–
4.32 (d, J = 10.5 Hz, 1 H), 4.34–4.42 (d, J = 11.3 Hz, 1 H),
4.48–4.56 (d, J = 12.0 Hz, 1 H), 4.58–4.65 (d, J = 11.3 Hz, 1
H), 6.64–6.71 (d, J = 8.3 Hz, 2 H), 7.03–7.10 (d, J = 8.3 Hz,
2 H), 7.17–7.27 (m, 5 H), 7.29–7.41 (m, 6 H), 7.59–7.68 (d,
J = 7.5 Hz, 4 H). 13C NMR (75 MHz, CDCl3): d = 0.1, 15.7,
18.5, 18.8, 19.2, 26.8, 27.0, 27.5, 27.7, 28.8, 33.4, 33.7, 35.8,
36.1, 37.1, 55.1, 68.7, 72.2, 72.4, 74.0, 75.9, 79.9, 80.0, 82.9,
85.7, 99.9, 105.8, 108.2, 113.5, 127.3, 127.5, 127.7, 128.2,
129.0, 129.4, 131.2, 133.9, 135.5, 138.5, 158.8. HRMS
(ESI): m/z [M + Na]+ calcd for C54H76O6Si2: 899.5078;
found: 899.5051.
(7) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett.
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Abraham, S.; Reddy, M. M.; Sabitha, G.; Sankar, A. R.;
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(16) Analytical Data for Compound 21:
Viscous liquid; [a]D25 –15.098 (c = 0.25, CHCl3). IR (Neat):
3310, 2950, 2885, 2097, 1736, 1612, 1513, 1463, 1362,
1247, 1081, 837, 773, 632 cm–1. 1H NMR (400 MHz,
CDCl3): d = 0.01 (s, 3 H), 0.02 (s, 3 H), 0.06 (s, 3 H), 0.07
(s, 3 H), 0.74 (d, J = 6.5 Hz, 3 H), 0.88 (s, 9 H), 0.92 (s, 9 H),
0.94 (d, J = 6.5 Hz, 3 H), 0.97 (d, J = 6.5 Hz, 3 H), 0.85–1.08
(m, 3 H), 1.40–1.55 (m, 2 H), 1.66–1.91 (m, 4 H), 1.94–2.06
(m, 1 H), 2.07–2.17 (m, 2 H), 2.90 (dd, J = 7.3, 11.7 Hz, 1
H), 3.08–3.17 (m, 1 H), 3.33–3.41 (m, 1 H), 3.52–3.58 (m, 1
H), 3.67–3.75 (m, 1 H), 3.79 (s, 3 H), 3.93 (dd, J = 3.6, 10.2
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(12) (a) Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem.
1999, 64, 4537. (b) Dess, D. B.; Martin, J. C. J. Org. Chem.
1983, 48, 4155. (c) Dess, D. B.; Martin, J. C. J. Am. Chem.
Soc. 1991, 113, 7277.
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Hz, 1 H), 4.25 (d, J = 10.2 Hz, 1 H), 4.51 (d, J = 10.9 Hz, 1
H), 4.62 (d, J = 11.7 Hz, 1 H), 4.69 (d, J = 12.4 Hz, 1 H), 6.79
(d, J = 8.7 Hz, 2 H), 7.17 (d, J = 8.7 Hz, 2 H), 7.23–7.31 (m,
5 H). 13C NMR (75 MHz, CDCl3): d = –4.7, –4.5, –4.2, –3.1,
16.6, 17.9, 18.9, 19.2, 25.6, 25.9, 26.7, 28.7, 31.3, 31.4, 35.2,
38.6, 55.2, 57.4, 69.3, 70.4, 71.7, 71.9, 75.7, 77.8, 80.3, 83.0,
113.5, 120.4, 127.0, 127.3, 128.1, 128.7, 131.5, 139.5,
158.8. HRMS (ESI): m/z [M + Na]+ calcd for
MHz, CDCl3): d = 17.0, 17.8, 19.7, 25.9, 28.8, 31.4, 36.2,
37.0, 44.3, 44.5, 57.6, 68.3, 69.7, 71.9, 73.8, 78.6, 82.5,
127.9, 128.2, 128.5, 137.8, 213.9. HRMS (ESI): m/z [M +
Na]+ calcd for C24H35N3O4: 452.2525; found: 452.2512.
(18) Analytical data for Compound 5 (Major Diastereomer):
Liquid; [a]D25 –18.801 (c = 0.6, CHCl3). IR (Neat): 3418,
2925, 2097, 1665, 1622, 1553, 1527, 1383, 1111, 616 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.92 (d, J = 7.1 Hz, 3 H),
0.99 (d, J = 6.2 Hz, 3 H), 1.01 (d, J = 7.1 Hz, 3 H), 1.39 (s,
1 H), 1.54–1.73 (m, 3 H), 1.77–2.05 (m, 4 H), 2.07–2.23 (m,
4 H), 2.55 (d, J = 7.1 Hz, 1 H), 3.07 (dd, J = 6.2, 11.6 Hz, 1
H), 3.18 (s, 3 H), 3.24 (dd, J = 6.2, 11.6 Hz, 1 H), 3.85–3.91
(m, 1 H), 3.95 (dd, J = 3.5, 6.2 Hz, 1 H), 4.37–4.44 (m, 1 H),
4.65 (d, J = 11.6 Hz, 1 H), 4.77 (d, J = 11.6 Hz, 1 H), 7.27–
7.40 (m, 5 H). 13C NMR (100 MHz, CDCl3): d = 16.3, 18.8,
19.2, 26.2, 28.7, 32.1, 32.4, 36.9, 37.0, 43.3, 47.7, 57.5, 69.6,
72.4, 72.5, 76.2, 82.8, 83.2, 111.2, 127.6, 127.9, 128.3,
138.5. HRMS (ESI): m/z [M + Na]+ calcd for C25H37N3O4:
466.2681; found: 466.2680.
C44H73N3O5Si2: 802.4986; found: 802.4968.
(17) Analytical data for Compound 22:
Liquid; [a]D25 –47.136 (c = 1.1, CHCl3). IR (Neat): 3417,
2119, 1618, 1389, 1204, 772 cm–1. 1H NMR (400 MHz,
CDCl3): d = 0.95 (d, J = 6.5 Hz, 3 H), 1.06 (d, J = 6.5 Hz, 3
H), 1.09 (d, J = 6.5 Hz, 3 H), 1.23–1.36 (m, 2 H), 1.45–1.71
(m, 3 H), 1.74–2.05 (m, 3 H), 2.18 (dd, J = 2.1, 5.8 Hz, 2 H),
2.61 (m, 1 H), 2.68 (d, J = 5.8 Hz, 2 H), 3.07–3.21 (m, 2 H),
3.40 (m, 1 H), 3.64–3.71 (m, 1 H), 3.74 (s, 0.5 H), 3.85 (s,
0.5 H), 4.07–4.15 (m, 1 H), 4.52 (d, J = 11.7 Hz, 1 H), 4.68
(d, J = 11.7 Hz, 1 H), 7.27–7.41 (m, 5 H). 13C NMR (75
Synlett 2007, No. 14, 2262–2266 © Thieme Stuttgart · New York

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