Synthesis of spirastrellolide A fragments for structure elucidation

Article abstract of DOI:10.1055/s-2006-933144

A stereocontrolled synthesis of two diastereomeric C₁-C ₂₂ fragments of spirastrellolide A consistent with reported spectroscopic data has been achieved to aid in a complete configurational assignment of this structurally novel and p

Full text of DOI:10.1055/s-2006-933144

LETTER
853
Synthesis of Spirastrellolide A Fragments for Structure Elucidation
S
C1–CuSpirastrell
e
Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas,
TX 75390-9038, USA
Fax +1(214)6480320; E-mail: jdebra@biochem.swmed.edu
Received 24 January 2006
spirastrellolide A
Abstract: A stereocontrolled synthesis of two diastereomeric C1–
MeO2C
C22 fragments of spirastrellolide A consistent with reported spectro-
Me
scopic data has been achieved to aid in a complete configurational
assignment of this structurally novel and potent antimitotic natural
product. A highly convergent coupling of two enantiomeric C1–C10
methyl ketone fragments with an enantiopure C11–C22 spiroketal
aldehyde produced the C1–C22 fragments with a longest linear se-
quence of 13 steps from commercially available starting materials.
OH
O
O
OMe
Cl
1
O
O
O
1: R = H, spirastrellolide A
2: R = Me
O
OH OH
8
9
OH
OH
OMe
Me
Me
cis-THP
Key words: total synthesis, natural products, spiro compounds,
asymmetric synthesis, structure elucidation
O
22
O
CO2Me
1
Given our fascination with structurally novel bioactive
natural products, we became interested in spirastrellolide
A – a potent antimitotic macrolactone isolated from ex-
tracts of a Caribbean marine sponge by Andersen and co-
workers.1 A revised and more complete structure of
spirastrellolide A was reported in a subsequent manu-
script, which also included data related to its ability to po-
tently inhibit protein phosphatase 2A (PP2A).2 Although
the relative stereochemistry within the C3–C7 (cis) and the
C9–C24 fragments has been elucidated, the relative stereo-
chemistry between these fragments remains uncertain.2
CO2Me
3
1
O
O
5: C3-S, C7-R
ent-5: C3-R, C7-S
3
O
OH OH
7
Me
10
8
7
9
11
OHC
Me
OPMB
OMe
11
O
22
O
Me
OPMB
22
O
3: C3-S, C7-R
4: C3-R, C7-S
O
6
OMe
Figure 1 A convergent approach for the synthesis of two diastereo-
meric C1–C22 fragments of spirastrellolide A
As shown in Figure 1, we targeted two alternative C1–C22
fragments 3 and 4 that represent the two diastereomers ally more practical, and also provided slightly better ee in
compatible with the published structural information.3,4 comparison to B-allyl bis(2-isocaranyl)borane.9,10 From
These diastereomers in turn would be available through a ent-8 (92% ee),11 the cis-substituted tetrahydropyran ent-
substrate-controlled 1,3-anti Mukaiyama aldol reaction of 5 was prepared according to the synthesis of 5.
enantiomerically pure spiroketal aldehyde 6 with the two
A short and convergent synthesis of key spiroketal frag-
enantiomeric cis-tetrahydropyranyl fragments 5 and ent-
ment aldehyde 6 from alkyne 11 and Weinreb amide 12 is
5, followed by a 1,3-anti-b-hydroxy ketone reduction. An
shown in Scheme 2. Alkyne 11 was readily available from
added advantage of this convergent approach is that it
known alcohol 1312 via (1) silylation (TESCl, imidazole,
allows for the synthesis of additional stereoisomers (C9,
C11) in the linker region connecting the cis-THP and the
spiroketal fragments.
CO2Me
CO2Me
OH
CO2Me
O
KOtBu, THF,
4-dIcr2BAll
ref. 7a
–35 °C (ref. 7a)
The synthesis of the two enantiomeric cis-tetrahydro-
pyranyl fragments 5 and ent-5 is shown in Scheme 1, and
is based on a final Wacker oxidation of allyl-substituted
tetrahydropyranyl derivative 9 to yield methyl ketone 5 in
70% yield.5 Previously, we had reported the synthesis of
compound 9, where the intermediate 8 was synthesized
from 7 using Brown’s B-allyl bis(4-isocaranyl)borane in
92% ee.6,7 However, for the preparation of ent-8, we
found Leighton’s allyl silane reagent 108 to be operation-
70%, 92% ee
80%
CHO
7
8
9
p-BrBn
N
cat. PdCl2, CuCl
O2, H2O, DMF
Cl
74%
92% ee
70%
Si
N
p-BrBn
10
CO2Me
CO2Me
CO2Me
OH
O
O
O
O
Me
Me
SYNLETT 2006, No. 6, pp 0853–0856
0
4.
0
4.
2
0
0
6
ent-8
ent-5
5
Advanced online publication: 14.03.2006
DOI: 10.1055/s-2006-933144; Art ID: S00506ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Synthesis of methyl ketones 5 and ent-5

854
Y. Pan, J. K. De Brabander
LETTER
DMF, 95%); (2) ozonolysis of the terminal olefin to give underwent acid-promoted desilylation of all three silyl
the aldehyde 14 (ozone, CH2Cl2; then PPh3, 80%); and (3) protecting groups followed by spiroketalization – provid-
Ohira–Bestmann homologation of aldehyde 14 (dimethyl- ing spiroketal 19 in 91% yield. Spiroketal 19 benefits
1-diazo-2-oxopropylphosphonate, K2CO3, MeOH, 0 °C from maximal anomeric stabilization, and its configura-
to r.t., 64%).13 For the synthesis of Weinreb amide 12, tion was confirmed by a strong NOE between H13 and
known epoxide 1514 was ring-opened with the sodium H21.17 The chemical shift of C17 (d = 93.97 ppm) is also
salt of p-methoxybenzyl alcohol (neat p-MeOBnOH, very close to that of the natural product (d = 93.8 ppm).
20 mol% NaH, 15, 70 °C, 8 h, 70%), followed by TES Finally, Swern oxidation of alcohol 19 gave the key cou-
protection to yield olefin 16. Ruthenium-catalyzed hydro- pling partner aldehyde 6 (78%).
esterification of alkene 16 with pyridylmethyl formate
We proceeded to explore the union of spiroketal 6 and
both mirror image methyl ketones 5 and ent-5 (Scheme 3).
According to the structure assignment of natural spira-
strellolide A, the relative C11,C13-anti configuration was
according to a procedure developed by Chang and co-
workers gave 2-pyridylmethyl ester 17 (73%).15 Forma-
tion of the branched isomer was not observed. Conversion
of 17 to the corresponding Weinreb amide 12 was accom-
required – a stereochemical outcome best achieved via a
plished in high yield by treatment with the magnesium
Mukaiyama aldol reaction.18 As expected, aldehyde facial
amide derived from N,O-dimethylhydroxylamine
bias predominated and provided the 1,3-anti aldol prod-
[(MeO)MeNH·HCl, 2 equiv i-PrMgCl, THF; then 17,
ucts 20 and 21 as the major stereoisomers (11:1 dr for 20;
92%].
7.7:1 dr for 21).19,20 Subsequent hydroxy-directed reduc-
Lithiation of akyne 11, followed by the addition of amide tion of b-hydroxy ketones 20 and 21 gave the correspond-
12 provided the desired coupling product 18 in 82% ing 1,3-anti diols [Me4N(AcO)3BH, MeCN, H2O, 80%],21
yield.16 This material was subjected to Lindlar reduction which were oxidatively deprotected (DDQ, CH2Cl2, H2O,
to give an intermediate Z-alkene (85%) that upon treat- 70%) to yield the two diastereomeric C1–C22 fragments 3
ment with p-toluenesulfonic acid in a THF–water mixture and 4.22
1
The H NMR and 13C NMR data of 3 and 4 were
compared to that of spirastrellolide A methyl ester 2
(Figure 2). In agreement with the data published by
OTBS
OHC
PMBO
11
11
22
TESO
Me
OPMB
22
Me
N
Paterson for C1–C24 fragments with similar relative
O
Me
O
17
stereochemistry in the C1–C20 region,3 neither 3 or 4
OTES
MeO
OMe
17
O
OMe
6
16 11
12
OHC
11
CO2Me
CO2Me
1
1
O
O
Me
PMBO
OTBS
OTBS
P
O
22
MeO
MeO
Me
O
O
O
O
O
1. TESCl, imidazole,
DMF
N2
17
Me
Me
2. O3, CH2Cl2, PPh3
K2CO3, MeOH
Me
Me
OMe
10
5
ent-5
OH
OTES
11
6
76%
76%
O
13
14
2,6-Lutidine, TMSOTf,
60%
51%
CH2Cl2, then 6, BF3·Et2O
11:1 dr
7.7:1 dr
1. NaH, PMBOH
2. TESCl, imidazole,
DMF
PMBO
Ru3(CO)12
(2-py)CH2O2CH
PMBO
CO2Me
CO2Me
22
O
TESO
TESO
1
1
3
3
17
73%
X
63%
O
O
OH
O
O
OH
OMe
15
OMe
OMe
O
16
7
9
7
9
92%
11
11
(MeO)MeNH, 17: X = -OCH2(2-py)
Me
PMBO
Me
PMBO
O
O
iPrMgCl, THF
12: X = -N(OMe)Me
22
22
O
O
20
21
OTBS
OTES
OMe
OMe
55%, 2 steps
1. Lindlar cat.,
quinoline, H2
2. p-TsOH, THF, H2O
BuLi, THF
1. Me4N(AcO)3BH, MeCN, HOAc
2. DDQ, CH2Cl2, pH 7 buffer
PMBO
TESO
11
55%, 2 steps
CO2Me
12
Me
CO2Me
OMe
78%
82%
3
3
O
18
O
OH OH
O
OH OH
NOE
OHC
11
HO
Me
7
9
7
9
H
13
Me
OPMB
22
(COCl)2, DMSO,
Et3N, CH2Cl2
Me
OH
22
Me
OH
22
O
O
H
O
O
O
21
O
O
OPM B
OMe
O
17
3
4
78%
OMe
6
19
OMe
OMe
Scheme 2 Synthesis of alkyne 11 and Weinreb amide 12, followed
by coupling and transformation to spiroketal 6
Scheme 3 Synthesis of two diastereomeric C1–C22 fragments by
coupling of aldehyde 6 with methyl ketones 5 and ent-5
Synlett 2006, No. 6, 853–856 © Thieme Stuttgart · New York

LETTER
Synthesis of C1–C22 Spirastrellolide Fragments
855
1
(3) Paterson and coworkers have recently reported the synthesis
of two diastereomeric C1–C25 fragments, see: Paterson, I.;
Anderson, E. A.; Dalby, S. M.; Loiseleur, O. Org. Lett. 2005,
7, 4125.
(4) For other synthetic studies, see: (a) Paterson, I.; Anderson,
E. A.; Dalby, S. M.; Loiseleur, O. Org. Lett. 2005, 7, 4121.
(b) Paterson, I.; Anderson, E. A.; Dalby, S. M. Synthesis
2005, 3225. (c) Liu, J.; Hsung, R. P. Org. Lett. 2005, 7,
2273. (d) Wang, C.; Forsyth, C. J. Abstracts of Papers,
229th ACS National Meeting, San Diego, CA, United States,
March 13-17, 2005, ORGN-414.
exhibited a close H NMR match to spirastrellolide, al-
though compound 4 resembled the natural product better
than 3 at H7, H8a and H9. This closer resemblance with
compound 4 is also seen by comparison of 13C NMR
shifts. However, it is still too early to conclude that 4
possesses the same stereochemistry as the natural product
due to discrepancies at H8b, H12b and C12. It is possible
that these discrepancies arise due to conformational
restriction when this fragment is embedded within the
spirastrellolide macrolactone. We are currently exploring
the incorporation of fragments 3 and 4 into macrolactones
to address this issue.23
(5) All new compounds gave spectroscopic data in agreement
with the assigned structures.
(6) Brown, H. C.; Randad, R. S.; Bhat, K. S.; Zaidlewicz, M.;
Racherla, U. S. J. Am. Chem. Soc. 1990, 112, 2389.
(7) Compound 9 was an intermediate in our synthesis of SCH
351448, see: (a) Bhattacharjee, A.; Soltani, O.; De
Brabander, J. K. Org. Lett. 2002, 4, 481. (b) Soltani, O.; De
Brabander, J. K. Org. Lett. 2005, 7, 2791.
(8) Kubota, K.; Leighton, J. L. Angew. Chem. Int. Ed. 2003, 42,
946.
(9) 2-dIcr2Ball is enantiocomplimentary to 4-dIcr2Ball, the
enantiomer of which is not available, see ref. 6.
(10) Paterson and coworkers have prepared the ethyl ester
analogue of ent-9 based on our7a route to 9 using 2-dIcr2Ball
in 90% ee, see ref. 3.
(11) For ee determination, see Supporting Information of ref. 7a.
(12) Prepared in three steps from commercially available 1,3-
propanediol, see: Theodorakis, E. A.; Drouet, K. E. Chem.
Eur. J. 2000, 6, 1987.
(13) (a) Ohira, S. Synth. Commun. 1989, 19, 561. (b) Müller, S.;
Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521.
(14) Prepared in two steps from commercially available divinyl
carbinol, see: (a) Romero, A.; Wong, C.-H. J. Org. Chem.
2000, 65, 8264. (b) Okamoto, S.; Kobayashi, Y.; Kato, H.;
Hori, K.; Takahashi, T.; Tsuji, J.; Sato, F. J. Org. Chem.
1988, 53, 5590.
(15) (a) Ko, S.; Na, Y.; Chang, S. J. Am. Chem. Soc. 2002, 124,
750. (b) Wang, L.; Floreancig, P. E. Org. Lett. 2004, 6, 569.
(c) Wang, L.; Floreancig, P. E. Org. Lett. 2004, 6, 4207.
(16) To a solution of 11 (0.158 g, 0.444 mmol) in anhyd THF
(3 mL) at –78 °C under nitrogen was added n-BuLi (2.5 M
in hexane, 0.19 mL, 0.48 mmol) and the solution turned
bright yellow. The reaction mixture was stirred at r.t. for
10 min before being cooled to –78 °C. A solution of the
Weinreb amide 12 (0.229 g, 0.488 mmol) in THF (1.5 mL)
was added dropwise, after which the mixture was warmed to
r.t. and stirred for an additional 1.5 h. The reaction was
quenched with sat. aq NH4Cl (15 mL) and extracted with
EtOAc (3 × 15 mL). The organic layers were combined,
dried over Na2SO4 and concentrated. The residue was puri-
fied by column chromatography (hexanes–EtOAc, 20:1 to
15:1) to give the product 18 as a colorless oil (0.278 g, 82%).
[a]D25 –4.9 (c 2.7, CHCl3). 1H NMR (400 MHz, CDCl3):
d = 7.24 (2 H, d, J = 8.8 Hz), 6.86 (2 H, d, J = 8.8 Hz), 4.43
(2 H, s), 3.93 (1 H, dt, J = 8.0, 4.0 Hz), 3.83 (1 H, dd, J = 9.6,
4.8 Hz), 3.79 (3 H, s), 3.62–3.69 (2 H, m), 3.37–3.48 (2 H,
m), 3.32 (3 H, s), 3.19 (1 H, dt, J = 8.0, 4.0 Hz), 2.73–2.80
(1 H, m), 2.54–2.70 (2 H, m), 1.76–1.87 (3 H, m), 1.66 (1 H,
td, J = 13.6, 6.0 Hz), 1.20 (3 H, d, J = 7.2 Hz), 0.95 (9 H, t,
J = 8.0 Hz), 0.92 (9 H, t, J = 8.0 Hz), 0.88 (9 H, s), 0.63 (6
Figure 2 Comparison of 1H NMR and 13C NMR chemical
shifts of 3 and 4 to those of spirastrellolide methyl ester 2
[dH/13C(3 or 4)–dH/13C(2)]
In summary, our synthesis of the C1–C22 fragment of
spirastrellolide A is highly convergent with a longest
linear sequence of 13 steps from commercially available
reagents. Further studies toward the synthesis of
spirastrellolide fragments and incorporation into fully
assembled macrolactones are currently underway, and
should ultimately lead to a full elucidation of spira-
strellolide stereochemistry.
Acknowledgment
This work was supported by the Robert A. Welch Foundation and
Merck Research Laboratories. J.K.D.B. is a fellow of the Alfred P.
Sloan Foundation.
References and Notes
H, q, J = 8.0 Hz), 0.58 (6 H, q, J = 8.0 Hz), 0.03 (6 H, s). 13
NMR (100 MHz, CDCl3): d = 188.1, 159.3, 130.5, 129.5,
113.9, 95.3, 82.4, 81.6, 73.2, 72.8, 71.9, 70.8, 59.7, 58.4,
55.4, 41.9, 37.0, 32.9, 26.1, 24.4, 18.4, 14.9, 7.1, 7.0, 5.2,
C
(1) Williams, D. E.; Roberge, M.; Van Soest, R.; Andersen, R.
J. J. Am. Chem. Soc. 2003, 125, 5296.
(2) Williams, D. E.; Lapawa, M.; Feng, X.; Tarling, T.;
Roberge, M.; Andersen, R. J. Org. Lett. 2004, 6, 2607.
5.1, –5.2, –5.2. IR: 2955, 2877, 1676, 1514, 1249, 1108, 834,
742 cm–1. MS (ESI): m/z = 773.60 (C40H74O7Si3Na).
Synlett 2006, No. 6, 853–856 © Thieme Stuttgart · New York

856
Y. Pan, J. K. De Brabander
LETTER
(17) Product 19 (colorless oil): [a]D25 +55.8 (c 2.18, CHCl3). 1H
NMR (400 MHz, CDCl3): d = 7.25 (2 H, d, J = 8.0 Hz), 6.84
(2 H, d, J = 8.0 Hz), 5.71 (1 H, d, J = 10.0 Hz), 5.58 (1 H, dd,
J = 10.0, 2.4 Hz), 4.52 (1 H, d, J = 12.0 Hz), 4.48 (1 H, d,
J = 12.0 Hz), 3.85–3.90 (1 H, m), 3.77 (3 H, s), 3.67–3.76 (4
H, m), 3.53 (1 H, dd, J = 10.0, 6.0 Hz), 3.27 (3 H, s), 3.15 (1
H, td, J = 9.6, 4.8 Hz), 2.11 (1 H, td, J = 7.2, 2.0 Hz), 2.02–
2.06 (1 H, m), 1.92–1.99 (1 H, m), 1.79–1.82 (1 H, m), 1.54–
1.73 (3 H, m), 0.95 (3 H, d, J = 7.2 Hz). 13C NMR (100 MHz,
CDCl3): d = 159.2, 135.4, 130.4, 129.5, 128.5, 113.7, 94.0,
74.8, 73.5, 73.0, 71.6, 69.4, 59.4, 56.4, 55.3, 35.1, 34.0, 33.6,
24.4, 16.7. IR: 3467, 2935, 1514, 1456, 1248, 1100, 1037,
985, 820 cm–1. MS (ESI): m/z = 415.15 (C22H32O6Na).
(18) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am.
Chem. Soc. 1996, 118, 4322.
2.68 (3 H, m), 2.33–2.52 (3 H, m), 2.09–2.13 (1 H, m), 2.01–
2.06 (1 H, m), 1.50–1.84 (9 H, m), 1.16–1.26 (2 H, m), 0.96
(3 H, d, J = 7.2 Hz). 13C NMR (100 MHz, CDCl3): d = 209.5,
171.9, 159.3, 135.3, 130.7, 129.6, 128.64, 113.8, 94.1, 74.7,
74.7, 74.6, 73.4, 73.1, 70.7, 69.3, 64.0, 56.4, 55.5, 51.9, 51.1,
50.4, 41.6, 39.6, 34.2, 33.8, 31.2, 31.0, 24.3, 23.3, 16.8. IR
3464, 2934, 1738, 1514, 1248, 1100, 1037, 985, 736 cm–1.
MS (ESI): m/z = 627.30 (C33H48O10Na).
(20) The absolute stereochemistry at C11 was confirmed via
Mosher ester derivatization (R- and S-esters) according to:
Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am.
Chem. Soc. 1991, 113, 4092.
(21) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem.
Soc. 1988, 110, 3560.
(22) Compound 3: [a]D25 +43.8 (c 0.16, CHCl3). 1H NMR (400
MHz, benzene-d6): d = 5.57–5.63 (2 H, m, H15, H16), 4.66 (1
H, app t, J = 7.6 Hz, H11), 4.17–4.21 (3 H, m, H9, H13, H21),
4.06 (1 H, dd, J = 11.6, 1.2 Hz, H22b), 3.86 (1 H, dd, J = 10.8,
5.6 Hz, H22a), 3.53–3.58 (1 H, m, H3), 3.45 (3 H, s, CO2Me),
3.20 (1 H, app t, J = 10.4 Hz, H7), 3.02 (3 H, s, OMe), 3.00–
3.05 (1 H, m, H20), 2.22 (1 H, dd, J = 14.8, 8.8 Hz, H2b),
(19) To a solution of ent-5 (36.7 mg, 0.171 mmol) and 2,6-
lutidine (140 mL, 1.20 mmol) in anhyd CH2Cl2 (1.2 mL) at
–78 °C was added dropwise trimethylsilyl trifluoro-
methanesulfonate (186 mL, 1.03 mmol). After stirring for 1.5
h at –78 °C, the reaction was quenched with sat. aq NaHCO3
(5 mL) and the aqueous phase was extracted with hexane (3
× 5 mL). The organic layers were combined, dried over
Na2SO4 and concentrated to give a colorless oil (46.0 mg).
This crude silylenol ether and aldehyde 6 (66.9 mg, 0.172
mmol) were dissolved in anhyd CH2Cl2 (1.1 mL) and cooled
to –78 °C. BF3·OEt2 (27.5 mL, 0.223 mmol) was slowly
added and the solution was stirred for 2 h at –78 °C. The
reaction was quenched with sat. aq NaHCO3 (5 mL) and the
aqueous phase was extracted with CH2Cl2 (3 × 5 mL). The
organic layers were combined, dried over Na2SO4 and
concentrated. The residue was purified by column
1.98–2.11 (2 H, m, H2a, H14), 1.84–1.94 (3 H, m, H12b, H18b
H19b), 1.72–1.76 (1 H, m, H19a), 1.60–1.69 (4 H, m, H8a, H8b,
10b, H12a), 1.48–1.52 (1 H, m, H18a), 1.36–1.39 (1 H, m,
,
H
H5b), 1.21 (1 H, d, J = 14.0 Hz, H10a), 1.06–1.12 (3 H, m, H4b,
H5a, H6b), 0.85–1.00 (2 H, m, H4a, H6a), 0.81 (3 H, d, J = 7.2
Hz). 13C NMR (75 MHz, benzene-d6): d = 171.3 (C1), 135.2
(C15), 129.3 (C16), 94.0 (C17), 79.4 (C7), 75.7 (C20), 74.7 (C3),
74.4 (C21), 71.1 (C13), 70.0 (C9), 65.2 (C11), 63.2 (C22), 55.8
(20-OMe), 51.4 (-CO2Me), 44.3 (C10), 43.1 (C8), 41.3 (C2),
40.9 (C12), 34.9 (C14), 34.3 (C18), 31.5 (C4), 30.9 (C6), 24.4
(C2), 23.2 (C5), 16.7 (14-Me). IR: 3450, 2933, 1738, 1438,
1090, 1044, 982 cm–1. MS (ESI): m/z = 509.5 (C25H42O9Na).
Compound 4: [a]D25 +46.7 (c 0.18, CHCl3). 1H NMR (400
MHz, benzene-d6): d = 5.59 (2 H, app s, H15, H16), 4.62 (1 H,
app t, J = 8.8 Hz, H11), 4.36 (1 H, br s, H9), 4.12–4.17 (2 H,
m, H13, H21), 4.05 (1 H, dd, J = 11.2, 1.6 Hz, H22b), 3.82 (1
H, dd, J = 11.2, 6.0 Hz, H22a), 3.61–3.66 (1 H, m, H3), 3.51–
3.55 (1 H, m, H7), 3.47 (3 H, s, CO2Me), 3.01 (3 H, s, 20-
OMe), 2.96–3.01 (1 H, m, H20) 2.33 (1 H, dd, J = 14.8, 8.8
Hz, H2b), 2.01–2.09 (2 H, m, H2a, H14), 1.80–1.93 (3 H, m,
H12b, H18b, H19b), 1.66–1.74 (2 H, m, H10b, H19a), 1.50–1.60
(3 H, m, H8a, H8b, H12a), 1.45–1.50 (2 H, m, H5b, H18a), 1.33–
1.39 (1 H, m, H10a), 1.08–1.19 (3 H, m, H4b, H5a, H6b), 0.86–
chromatography (hexanes–EtOAc, 2:1 to 2:3) to give, in
order of elution, the recovered methyl ketone ent-5 (12.3
mg), the minor 1,3-syn aldol product (6.0 mg, 8.7% based on
recovered starting material) and the 1,3-anti aldol product 21
(46.2 mg, 76% based on recovered starting material).
Compound 21: [a]D25 +24.3 (c 1.1, CHCl3). 1H NMR (400
MHz, CDCl3): d = 7.26 (2 H, d, J = 8.4 Hz), 6.86 (2 H, d,
J = 8.4 Hz), 5.71 (1 H, d, J = 9.6 Hz), 5.60 (1 H, dd, J = 9.6,
2.0 Hz), 4.55 (1 H, d, J = 12.0 Hz), 4.47 (1 H, d, J = 12.0
Hz), 4.39–4.45 (1 H, m), 3.80 (3 H, s), 3.77–3.84 (4 H, m),
3.66 (3 H, s), 3.64–3.68 (1 H, m), 3.55–3.60 (2 H, m), 3.28
(3 H, s), 3.18–3.23 (1 H, m), 2.62–2.69 (3 H, m), 2.36–2.52
(3 H, m), 2.10–2.14 (1 H, m), 2.01–2.05 (1 H, m), 1.51–1.84
(9 H, m), 1.15–1.23 (2 H, m), 0.97 (3 H, d, J = 7.2 Hz). 13
NMR (75 MHz, CDCl3): d = 209.6, 171.9, 159.2, 135.3,
C
0.96 (2 H, m, H4a, H6a), 0.81 (3 H, d, J = 6.8 Hz, 14-Me). 13
NMR (75 MHz, benzene-d6): d = 171.7 (C1), 135.3 (C15),
C
130.6, 129.6, 128.6, 113.8, 94.1, 74.8, 74.7, 74.5, 73.4, 73.1,
70.7, 69.3, 64.1, 56.4, 55.4, 51.9, 50.9, 50.4, 41.6, 39.6, 34.2,
33.8, 31.2, 30.9, 24.3, 23.3, 16.8. IR: 3490, 2933, 1739,
1514, 1248, 1100, 1036, 985, 821, 728 cm–1. MS (ESI):
m/z = 627.30 (C33H48O10Na).
Compound 20 was prepared using the same procedure in
59% yield and 11:1 dr; [a]D25 +27.0 (c 0.22, CHCl3). 1H
NMR (400 MHz, CDCl3): d = 7.26 (2 H, d, J = 8.4 Hz), 6.86
(2 H, d, J = 8.4 Hz), 5.71 (1 H, dd, J = 10.0, 1.6 Hz), 5.59 (1
H, dd, J = 10.0, 1.6 Hz), 4.55 (1 H, d, J = 12.0 Hz), 4.46 (1
H, d, J = 12.0 Hz), 4.39–4.45 (1 H, m), 3.80 (3 H, s), 3.75–
3.83 (4 H, m), 3.65 (3 H, s), 3.62–3.69 (2 H, m), 3.58 (1 H,
dd, J = 10.4, 5.6 Hz), 3.28 (3 H, s), 3.18–3.24 (1 H, m), 2.58–
129.2 (C16), 94.0 (C17), 75.9 (C20), 75.7 (C7), 74.6 (C3), 74.4
(C21), 71.0 (C13), 66.0 (C9), 65.1 (C11), 63.4 (C22), 55.7 (20-
OMe), 51.4 (CO2Me), 44.4 (C10), 43.0 (C8), 41.4 (C2), 40.6
(C12), 34.8 (C14), 34.2 (C18), 31.2 (C4), 31.0 (C6), 24.3 (C19),
23.6 (C5), 16.7 (14-Me). IR: 3440, 2933, 1738, 1440, 1200,
1091, 983 cm–1. MS (ESI): m/z = 509.5 (C25H42O9Na).
(23) A referee pointed out that an intact C1–C22 fragment is
potentially available from degradation of the natural
product. At this point, we have not yet contacted the
isolation group to explore the possibility for such
degradation studies on very limited amounts of natural
spirastrellolide.
Synlett 2006, No. 6, 853–856 © Thieme Stuttgart · New York