An efficient synthesis of the C1-C14 subunit of (-)-lasonolide A via a target oriented β-C-glycoside formation sequence

Article abstract of DOI:10.1016/j.tetlet.2005.11.156

An efficient synthesis of the C₁-C₁₄ subunit resident in (-)-lasonolide A is reported herein. The key reaction features that were utilized include a Molander-Reformatsky SmI₂ mediated intramolecular aldol reaction followed

Full text of DOI:10.1016/j.tetlet.2005.11.156

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 939–942
An efficient synthesis of the C1–C14 subunit of (À)-lasonolide A
via a target oriented b-C-glycoside formation sequence
Kailas B. Sawant, Fei Ding and Michael P. Jennings*
Department of Chemistry, 500 Campus Drive, The University of Alabama, Tuscaloosa, AL 35487-0336, USA
Received 14 November 2005; revised 22 November 2005; accepted 29 November 2005
Available online 19 December 2005
Abstract—An efficient synthesis of the C1–C14 subunit resident in (À)-lasonolide A is reported herein. The key reaction features that
were utilized include a Molander–Reformatsky SmI2 mediated intramolecular aldol reaction followed by a diastereoselective target
oriented b-C-glycoside formation sequence. Lastly, a chemo- and diastereoselective cross-metathesis of a terminal olefin in the pres-
ence of a trisubstituted alkene with acrolein and subsequent olefination of the aldehyde moiety allowed for the completion of the
(E,E)-diene side chain.
Ó 2005 Published by Elsevier Ltd.
Over the past two decades, the construction of a- and b-
C-glycosides has become increasingly important in the
synthesis of biologically active natural products. Along
this line, there has been substantial growth in new syn-
thetic methodologies within this area. Such building
blocks have been synthesized by using several technolo-
gies including the hetero-atom Diels–Alder reaction,1
Petasis–Ferrier rearrangement,2 intermolecular silyl-
modified Sakurai and Prins cyclizations,3 exo-Pd-medi-
ated allylic etherification,4 radical cyclization,5 and
intramolecular Michael additions with oxygen nucleo-
philes.6 As a complementary procedure to these techno-
logies, our research program is interested in expanding
and concomitantly defining a broader scope of KishiÕs
strategy for the synthesis of b-C-glycosides.7
reported to date.5,10 Lee and co-workers were the first
to disclose the asymmetric total synthesis of 1, in addi-
tion to a structural revision, thus determining both the
relative and absolute configuration of natural (À)-laso-
nolide.5 Key steps in their synthesis included two radical
cyclizations to form both b-C-glycoside units followed
by a Yamaguchi macrocyclization. Subsequently, Kang
and co-workers reported the second total synthesis of 1,
by utilizing a clever desymmetrization followed by an
asymmetric allylation en route to the completion of
the upper b-C-glycoside subunit and then ultimately 1.10
As shown in Scheme 1, our initial approach to the syn-
thesis of 1 was based on a stereoselective reduction of a
cyclic oxocarbenium cation mediated by the treatment
of an appropriate hemi-ketal with Lewis acid. In turn,
the hemi-ketal was envisaged to be derived from a nucleo-
philic addition of the allyl Grignard reagent to the cor-
responding lactone 3. We envisioned a SmI2 Molander–
Reformatsky11 lactonization sequence for the synthesis
of 3, which would be derived ultimately from the a,b-
unsaturated aldehyde 4.
First isolated from Forcepia sp. in 1994 by McConnell,
(À)-lasonolide A (1) represents a potent anti-tumor
agent which exhibits significant cytotoxic activity (ng/
ml) against P388 murine leukemia, A-549 human lung
carcinoma cell lines, and inhibits cell adhesion in the
EL-4.IL-2 cell line.8 In addition to the impressive levels
of biological activity, the highly unique structure of 1
makes it an attractive target for total synthesis and an
ideal target for testing synthetic methodologies of b-C-
glycosides. Thus, a variety of synthetic approaches to
1 have been reported9 with only two total syntheses
The synthesis of 2 was initiated with the previously
reported a,b-acetylenic ester 5,12 as shown in Scheme
2. Thus, carbocupration of 5 utilizing the dimethyl
Gilman reagent (Me2CuÀ Li+) under CoreyÕs condi-
tions13 allowed for the stereoselective formation of the
trisubstituted a,b-unsaturated ester 6 in 91% yield. Sub-
sequent reduction of the ester moiety with DIBAL fur-
nished the primary alcohol, which in turn was oxidized
*
Corresponding author. Tel.: +1 205 348 0351; fax: +1 205 348
9104; e-mail: jenningm@bama.ua.edu
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.11.156

940
K. B. Sawant et al. / Tetrahedron Letters 47 (2006) 939–942
Wittig Olefination
O
OTBDPS
a) Et3N
Br
OTBDPS
TBSO
OH
OH
O
Olefination
O
28
O
TBSO
10
Br
O
O
O
11
Br
b) PPTS, EtOH
OTBDPS
HO
14
OEt
1
14
O
O
O
O
Br
OTBDPS
Br
OTBDPS
esterificatio3n
4
O
O
O
c) Dess-Martin
O
OHC
HO
OH
12
13
OTES
1
2
Scheme 3. Synthesis of the bromoacetyl-aldehyde 13: Reagents and
conditions: (a) bromoacetyl bromide (2.0 equiv), Et3N (2.5 equiv),
DMAP (0.03 equiv), CH2Cl2, 0 °C, 2 h, 85%; (b) PPTS (0.3 equiv), EtOH,
rt, 72 h, 88%; (c) Dess–Martin periodinane (1.5 equiv), CH2Cl2, 0 °C, 3 h,
55%. PPTS = pyridinium p-toluenesulfonate; Dess–Martin period-
inane = 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxo-3-(1H)-one.
O
OTBDPS
OTBDPS
14
14
O
O
H
HO
4
3
Scheme 1. Retrosynthesis of (À)-lasonolide A.
syn-aldol adduct 8 with a 90% yield and P97:3 dr as
determined by 1H NMR. With the requisite stereochem-
istry from the aldol product 8 in hand, removal of the
EvansÕ auxiliary was accomplished via treatment of 8
with NaBH4 in a 1/1 THF/H2O solvent mixture as
reported by Prashad16 to provide the diol 9 in 88% yield.
Much to our surprise treatment of 9 with TBSCl and
imidazole did not lead to selective silylation of the pri-
mary hydroxyl moiety. Finally, discrimination between
the primary and secondary alcohol was realized and
the silylation was accomplished in 80% yield upon treat-
ment of 9 with TBSCl, Et3N, and DMAP in CH2Cl2 to
furnish intermediate 10.
TBDPSO
OTBDPS
O
a) MeLi, CuI
MeO
b) DIBAL
6
MeO
O
c) TPAP-NMO
5
OTBDPS
O
O
N
OH
OTBDPS
O
d)
n
BuBOTf, Et3N
O
O
O
H
Bn
8
4
N
O
e) NaBH4
Bn
7
With the two hydroxyl moieties of 9 differentiated via the
selective silylation of the primary alcohol, we turned our
attention to the introduction of the bromo-acetate func-
tionality in order to examine the feasibility of the pro-
posed stereoselective intramolecular Reformatsky
lactone formation reaction sequence. With this in mind,
esterification of the free secondary hydroxyl moiety resi-
dent in 10 was accomplished with bromoacetyl bromide,
Et3N, and DMAP in 85% yield as shown in Scheme 3.
Subsequent selective TBS desilylation of 11 was achieved
by utilizing PPTS in EtOH to afford the free primary hy-
droxyl intermediate 12. Unfortunately oxidation of the
primary alcohol resident in 12 to the labile aldehyde 13
was problematic. Treatment of 12 with a variety of oxida-
tion protocols such as TEMPO–BAIB, TPAP–NMO,
and Swern provided the a,b-unsaturated aldehyde via
b-elimination of the bromoacetyl group.17 Much to our
delight, oxidation of 12 readily afforded aldehyde 13
via the Dess–Martin reagent in an acceptable 55% yield.
OTBDPS
f) TBSCl
OTBDPS
OH OH
TBSO
OH
9
10
Scheme 2. Synthesis of intermediate 10: Reagents and conditions: (a)
CuI (1.5 equiv), THF, 0 °C, MeLi (3 equiv), 10 min, then À78 °C, then
5, 4 h, 91%; (b) DIBAL (2.2 equiv), Et2O, À78 to 0 °C, 3 h, 92%; (c)
TPAP (5 mol %), NMO (2.1 equiv), CH2Cl2, 0 °C, 2 h, 96%; (d) 7
(1.15 equiv), CH2Cl2, À55 °C, n-BuBOTf (1.19 equiv), 30 min, Et3N
(1.3 equiv), 20 min, 0 °C, then 4, À70 °C, 4 h, 90%; (e) NaBH4
(4 equiv), THF/H2O: 1/1, rt, 3.5 h, 88%; (f) TBSCl (1.15 equiv), Et3N
(3.1 equiv), DMAP (0.30 equiv), CH2Cl2, 12 h, 80%. DIBAL = di-
isobutyl-aluminum hydride; TPAP = tetrapropylammonium perruthe-
nate; NMO = 4-methyl-morpholine-N-oxide; TBSCl = tert-butyl-
dimethylsilylchloride; DMAP = 4-dimethylaminopyridine.
to aldehyde 4 by means of LeyÕs TPAP reagent14 with a
combined yield of 90% over the two steps from ester 6.
With 4 in hand, our attention was turned to the initial
introduction of the syn-stereochemistry as required for
the completion of 2. This aspect was uneventfully
accomplished by the treatment of aldehyde 4 with the
benzyl substituted oxazolidinone 7. Accordingly, enoli-
zation of 7 was achieved under the EvansÕ protocol15
utilizing the standard reagents such as n-Bu2BOTf
and Et3N followed by treatment of the pre-formed
(Z)-boron enolate with aldehyde 4 which provided the
With 13 in hand, the stage was set for the intramolecular
SmI2 mediated Reformatsky sequence. Molander re-
ported that the treatment of a bromoacetyl moiety with
SmI2 readily allowed for the synthesis of a Sm(III) eno-
late which subsequently underwent an intramolecular
aldol reaction with a pendent aldehyde via a double
six-membered transition state to furnish selectively a b-
hydroxy lactone with exceptional diastereoselectivity.11

K. B. Sawant et al. / Tetrahedron Letters 47 (2006) 939–942
941
O
OSm(III)
O
O
Br
OHC
OTBDPS
a) SmI2
O
OTBDPS
OTBDPS
OTBDPS
a) allylMgBr
OH
O
OTBDPS
O
OHC
HO
13
HO
14
3
15
O
O
TFA
H
OTBDPS
SmIII
O
O
O
H
HO
H
OTBDPS
3
OTBDPS
Me
+
O
O
Et3SiH
Scheme 4. Synthesis of lactone 3: Reagents and conditions: (a) SmI2
(2.0 equiv), THF, 0 °C, 2 h, 51%.
TESO
HO
17
b) acrolein, 18
16
O
O
H
EtO
As anticipated, treatment of 13 with SmI2 provided the
initial Sm(III) enolate intermediate which quickly under-
went cyclization to provide lactone 3 as a single diaste-
1
reomer as observed by H NMR in 51% yield via the
proposed transition state as shown in Scheme 4.18
OTBDPS
OTBDPS
O
O
c) 20
TESO
TESO
With the key hydroxy-lactone 3 in hand, our attention
was initially focused on the allyl b-C-glycoside forma-
tion followed by final elaboration of the terminal alkene
functional group into the final targeted structure 2.
Thus, treatment of lactone 3 with excess allyl magne-
sium bromide readily afforded the lactol intermediate
15 as a mixture of two diastereomers as observed by
1H NMR. Immediate addition of TFA to lactol 15 seem-
ingly provided the oxocarbenium intermediate 16, which
was subsequently reduced with Et3SiH. As observed in
our previous synthesis of (À)-dactylolide,7c the free sec-
ondary hydroxyl group was concomitantly protected as
a TES ether under the reductive conditions for the trans-
formation of 16 to 17. The overall yield of the five trans-
formations (nucleophilic addition, oxocarbenium
formation, Et3SiH reduction of the oxocarbenium cat-
ion, active silylating reagent formation, and silylation
of the free hydroxyl moiety) was a very respectable
44%. The remaining material balance was the untriethyl-
silylated compound of pyran 17. Chemo- and diastereo-
selective cross-metathesis of the terminal alkene with
acrolein utilizing the GrubbsÕ second-generation carbene
catalyst19 18 was accomplished with a 15:1 ratio in favor
of the predicted and desired (E)-a,b-unsaturated alde-
hyde 19 in 72% yield. The geometry of the two olefins
and the b-C-glycoside moiety were deduced via the
NOE enhancements as shown in Figure 1. In addition
to the NOE experiment, the observed coupling constants
19
18
2
O
N
N
OEt
20
Cl
Cl
Ph3P
Ru
PCy3
Ph
Scheme 5. Completion of subunit 2. Reagents and conditions: (a) (i)
allylMgBr (2.5 equiv), THF, À78 °C, 1 h, (ii) TFA (6 equiv), Et3SiH
(6 equiv), CH2Cl2, À78 °C, 2 h, 44%; (b) acrolein (2.0 equiv), 18
(5 mol %), CH2Cl2, 50 °C, 16 h, 72%; (c) 20 (2 equiv), THF, 0 °C to rt,
4 h, 82%. TFA = trifluoroacetic acid.
(14 Hz) of the unsaturated aldehyde protons provided
further geometrical proof of compound 19. Final elabo-
ration of the aldehyde moiety to the (E,E)-a,b-unsatu-
rated ester was accomplished upon treatment of 19
with the stabilized Wittig reagent 20 to ultimately fur-
nish 2 in an 82% yield (Scheme 5).20
In conclusion, we have completed the synthesis of the
C1–C14 subunit resident in (À)-lasonolide A. The key
reaction features that were utilized included a Molan-
der–Reformatsky SmI2 mediated intramolecular aldol
reaction followed by a diastereoselective target oriented
b-C-glycoside formation sequence. Lastly, a chemo- and
diastereoselective cross-metathesis of a terminal olefin in
the presence of a trisubstituted alkene with acrolein and
subsequent olefination of the aldehyde moiety allowed
for the completion of the (E,E)-diene side chain of 1.
Studies toward the total synthesis of 1 are ongoing
and will be reported in due course.
H
TBDPSO
H
H
OTES
H
O
H
H
Me
Acknowledgements
H
Support was provided by the University of Alabama
and the NSF (CHE-0115760), for the departmental
NMR facility.
H
O
Figure 1. Key NOE enhancements of intermediate 19.

942
K. B. Sawant et al. / Tetrahedron Letters 47 (2006) 939–942
10. (a) Kang, S. H.; Kang, S. Y.; Kim, C. M.; Choi, H.; Jun,
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18. Data for lactone 3: 1H NMR (500 MHz, CDCl3): d 7.7
(m, 4H), 7.4 (m, 6H), 5.3 (dd, J = 9, 1 Hz, 1H), 5.2 (dd,
J = 9, 3 Hz, 1H), 4.2 (s, 2H), 3.9 (dd, J = 9.5, 4.5 Hz, 1H),
2.8 (dd, J = 18, 5.5 Hz, 1H), 2.4 (dd, J = 18, 3.5 Hz,
1H), 1.7 (m, 1H), 1.9 (s, 3H), 1.1 (s, 9H), 0.9 (d, J = 7 Hz,
3H). 13C NMR (125 MHz, CDCl3): d 170.1, 140.7, 135.6,
133.2, 129.8, 127.9, 121.8, 74.6, 68.1, 62.6, 39.2, 36.0, 26.8,
21.3, 19.3, 10.8. IR (neat) 3450, 1721, 1428, 1112,
1062 cmÀ1. Rf = 0.2, 40% EtOAc in hexanes. HRMS
(EI) calculated for C26H34O4Si (M+): 438.2226, found:
438.2229.
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7.7 (m, 4H), 7.4 (m, 6H), 7.2 (dd, J = 15.5, 4.5 Hz, 1H),
6.2 (dd, J = 15, 11 Hz, 1H), 6.1 (m, 1H), 5.8 (d, J = 15 Hz,
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144.8, 140.3, 135.6, 132.6, 130.2, 129.5, 127.6, 125.6, 119.7,
71.2, 70.8, 70.5, 62.6, 60.2, 40.3, 39.6, 35.5, 29.9, 26.8, 22.0,
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