Synthesis of the C17-C25 subunit of lasonolide A utilizing a Tsuchihashi-Yamamoto type rearrangement

Article abstract of DOI:10.1016/j.tetlet.2007.05.160

An efficient synthesis of the C₁₇-C₂₅ subunit resident in (-)-lasonolide A is reported herein. The key reaction features that were utilized include a Tsuchihashi-Yamamoto type rearrangement and Molander-Reformatsky SmI₂ me

Full text of DOI:10.1016/j.tetlet.2007.05.160

Tetrahedron Letters 48 (2007) 5177–5180
Synthesis of the C17–C25 subunit of lasonolide A utilizing a
Tsuchihashi–Yamamoto type rearrangement
Kailas B. Sawant, Fei Ding and Michael P. Jennings*
Department of Chemistry, 500 Campus Drive, The University of Alabama, Tuscaloosa, AL 35487-0336, United States
Received 1 May 2007; revised 21 May 2007; accepted 25 May 2007
Available online 2 June 2007
Abstract—An efficient synthesis of the C17–C25 subunit resident in (ꢀ)-lasonolide A is reported herein. The key reaction features
that were utilized include a Tsuchihashi–Yamamoto type rearrangement and Molander–Reformatsky SmI2 mediated intramolecular
aldol reaction sequence. Lastly, a diastereoselective target oriented b-C-glycoside formation sequence via an oxocarbenium reduc-
tion completed the stereochemistry required for the completion of the C17–C25 segment of (ꢀ)-lasonolide A.
Ó 2007 Elsevier Ltd. All rights reserved.
The construction of a-and b-C-glycosides has become
increasingly important in the synthesis of biologically
active natural products. Consequently, there has been
substantial growth in the arena of new synthetic meth-
odologies within this area. Along this line, building
blocks have been synthesized by using several innovative
technologies including the hetero-atom Diels–Alder
reaction,1 Petasis–Ferrier rearrangement,2 intermolecu-
lar silyl-modified Sakurai and Prins cyclizations,3 exo-
Pd-mediated allylic etherification,4 radical cyclization,5
and intramolecular Michael additions with oxygen
nucleophiles.6 As a complementary procedure to these
technologies, our research program is interested in
expanding and concomitantly defining a broader scope
of Kishi’s strategy for the synthesis of b-C-glycosides.7
the asymmetric total synthesis of 1, in addition to a
structural revision, thus determining both the relative
and absolute configuration of natural (ꢀ)-lasonolide.5
Key steps in their synthesis included two radical cycliza-
tions to form both b-C-glycoside units followed by a
Yamaguchi macrocyclization. Subsequently, Kang
reported the second total synthesis of 1, by utilizing an
efficient desymmetrization followed by an asymmetric
allylation en route to the completion of the upper b-C-
glycoside subunit and then ultimately 1. In addition,
the Shishido and Ghosh groups have also recently com-
pleted the total synthesis of 1.10
As delineated in Scheme 1, our initial approach to the
synthesis of the C17–C25 portion of 1 was based on a
stereoselective reduction of a cyclic oxocarbenium cat-
ion mediated by the treatment of an appropriate hemi-
ketal with Lewis or protic acid. In turn, the hemi-ketal
was envisaged to be derived from a nucleophilic addition
of the allyl Grignard reagent to the corresponding lac-
tone 3. We envisioned a SmI2 Molander–Reformatsky11
lactonization sequence for the synthesis of 3, which
would be derived from b-hydroxy aldehyde 4. Finally,
the quaternary center resident in 4 was envisioned via
a Tsuchihashi–Yamamoto type rearrangement by means
of an appropriate chiral vinyl epoxide.12
First isolated from Forcepia sp. in 1994 by McConnell,
(ꢀ)-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 four total syntheses reported
to date.5,10 Lee and co-workers were the first to disclose
The synthesis of 2 was initiated with the previously
reported benzyl protected aldehyde 5,13 as shown in
Scheme 2. Thus, a stabilized Wittig olefination of the
aldehyde moiety of 5 with the commercially available
carbethoxymethylene phosphorane selectively provided
*
Corresponding author. Tel.: +1 205 348 0351; fax: +1 205 348
9104; e-mail: jenningm@bama.ua.edu
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.160

5178
K. B. Sawant et al. / Tetrahedron Letters 48 (2007) 5177–5180
Wittig Olefination
OH
BnO
OTMS
BnO
OH O
O
Lewis acid
H
Olefination
O
10
4
28
O
O
O
a) TiCl4
OTMS
Cl4Ti
HO
14
Cl4Ti
SiMe3
BnO
O
BnO
O
δ+
BnO
O
O
O
2
esterificatio3n
δ+
4
O
OTES
OH
Scheme 3. Synthesis of b-hydroxy aldehyde 4. Reagents and condi-
tions: (a) TiCl4 (1.5 equiv, 1 M soln), CH2Cl2, ꢀ78 °C, 1 h, 78%.
1
O
OH
BnO
O
O
H
BnO
to furnish 10 with a combined yield of 54% over three
steps from epoxy alcohol 8. With vinyl epoxide 10 in
hand, we turned our attention to the Tsuchihashi–
Yamamoto rearrangement as the means for the intro-
duction of the required chiral quaternary center of the
upper b-C-glycoside unit of 1.
3
4
OH
Scheme 1. Retrosynthesis of (ꢀ)-lasonolide A.
COOEt
BnO
BnO
O
As shown in Scheme 3, we envisioned that treatment of
10 with a Lewis acid would trigger a 1,2 vinyl migration
and proceed to provide the requisite b-hydroxy aldehyde
as reported by Tsuchihashi and Yamamoto.12 With this
in mind, addition of a 1 M solution of TiCl4 to the vinyl
epoxy intermediate 10 did indeed elicit the proposed 1,2-
vinyl migration and provided the desired b-hydroxy
aldehyde 4 in 78% yield with a 15:1 dr as determined
a)
PPh3
COOEt
H
O
6
5
b) LiAlH4
c) (+)-DET
Ti(OiPr)4
BnO
BnO
BnO
BnO
OH
OH
t
BuOOH
1
8
9
7
by H NMR.15
d) Dess-Martin
O
With 4 in hand, the stage was set for the intramolecular
SmI2 mediated Reformatsky sequence. Molander
reported that the treatment of a bromoacetyl moiety with
SmI2 readily allowed for the synthesis of a Sm(III)
enolate, which subsequently underwent an intramolecu-
lar aldol reaction with a pendent aldehyde via a double
six membered transition state to furnish selectively a b-
hydroxy lactone with exceptional diastereoselectivity.11
OTMS
O
e) vinylMgBr
O
H
f) TMSCl, imid.
10
Scheme 2. Synthesis of epoxy intermediate 10. Reagents and condi-
tions: (a) (carbethoxymethylene)triphenylphosphorane (1.2 equiv),
CH2Cl2, rt, 12 h, 84%. (b) LiAlH4 (1.1 equiv), Et2O, rt, 20 h, 90%.
(c) (+)-Diethyl tartrate (1.2 equiv), Ti(OiPr)4 (1.1 equiv), tBuOOH
(2.0 equiv), CH2Cl2, 0 °C, 6 h, 77%. (d) Dess–Martin periodinane
(1.5 equiv), CH2Cl2, rt, 2 h, 85%. (e) VinylMgBr (2.0 equiv), THF,
ꢀ20 °C, 1 h, 78%. (f) TMSCl (2.0 equiv), imid. (4.0 equiv), DMF, rt,
6 h, 82%. Dess–Martin periodinane = 1,1,1-tris(acetyloxy)-1,1-dihydro-
1,2-benziodoxo-3-(1H)-one; imid. = imidazole.
In order to investigate the feasibility of this reaction, we
transformed b-hydroxy aldehyde 4 into bromoester 11
in an acceptable 82% yield. As anticipated, treatment
of 11 with SmI2 provided the initial Sm(III) enolate
intermediate, which quickly underwent cyclization to
provide lactone 3 as a single diastereomer as observed
1
the (E)-a,b-unsaturated ethyl ester 6 in 84% yield. Ensu-
ing reduction of 6 with LiAlH4 readily furnished the
allylic alcohol 7 in 90% yield and set the stage for the
introduction of the initial chirality required for the com-
pletion of 2. Along this line, Sharpless’ asymmetric
epoxidation14 of the olefin moiety resident in alcohol 7
with the obligatory reagents (diethyl tartrate, Ti(OiPr)4,
and tBuOOH) afforded epoxy alcohol 8 in 77% yield
with an er of 96:4 as checked via the Mosher ester. Sub-
sequent oxidation of the primary hydroxyl group with
Dess–Martin periodinane provided the epoxy aldehyde
9, which was immediately transformed to the vinyl alco-
hol as a mixture of inconsequential diastereomers by
means of nucleophilic addition of the vinyl Grignard
reagent. Final protection of the free hydroxyl moiety as
a silyl ether was accomplished with TMSCl and imidazole
by H NMR in 83% yield via the proposed transition
state as shown in Scheme 4.16 Two observations are
worth noting. The first is that the a-chiral quaternary
center had little to no influence on the stereochemical
outcome of the Molander–Reformatsky reaction. Sec-
ondly, the inclusion of the a-chiral quaternary center
provided a greater yield (83%) than that of a lesser
substituted b-bromoacetate aldehyde, via the presumed
Thorpe–Ingold effect during cyclization.17
With the key hydroxy-lactone 3 in hand, our attention
was initially focused on the allyl b-C-glycoside forma-
tion followed by the final elaboration of the terminal
alkene functional group into the final targeted structure
14. Thus, treatment of lactone 3 with excess allyl magne-
sium bromide readily afforded the lactol intermediate as

K. B. Sawant et al. / Tetrahedron Letters 48 (2007) 5177–5180
5179
O
O
O
HO
O
Br
Br
BnO
OH
O
O
Br
BnO
O
a) allylMgBr
a)
BnO
O
BnO
pyridine
CHO
H
OH
OH
11
4
3
b) SmI2
Me
TFA
-
Si
H
O
O
BnO
O
H
Et3SiH
OBn
H
O
Me
+
H
+
OH
O
SmIII
O
O
HO
H
OBn
OBn
H-
3
15
Me
Scheme 4. Synthesis of lactone 3. Reagents and conditions: (a)
bromoacetyl-bromide (2.0 equiv), pyridine (3.0 equiv), CH2Cl2, 0 °C,
2 h, 82%. (b) SmI2 (2.5 equiv), THF, 0 °C, 1.5 h, 83%.
H
O
BnO
O
b) O3
a mixture of two diastereomers as observed by 1H
NMR. Immediate addition of TFA seemingly provided
the oxocarbenium intermediate 15, which was subse-
quently reduced with Et3SiH. As observed in our previ-
ous syntheses of (ꢀ)-dactylolide and diospongin A,7c,d
the free secondary hydroxyl group was concomitantly
protected as a TES ether under the reductive conditions
for the transformation of 3 to 2 via a proposed pentava-
lent siliconate intermediate. The overall yield of the four
transformations (nucleophilic addition, oxocarbenium
formation, active silylating reagent formation via the
proposed siliconate, and concomitant intramolecular
reduction of the oxocarbenium cation) was a very
respectable 66%.18 The global stereochemistry of the b-
C-glycoside intermediate 2 was deduced via the NOE
enhancements as shown in Figure 1. Oxidation of both
terminal olefins via O3, followed by an aqueous acid
workup, provided the deprotected bis-aldehyde com-
pound 12 in 95% yield. Final global reduction of the
bis-aldehyde moieties resident in 12 to triol 13 and ensu-
ing acetonide formation of the syn-1,3 diol with DMP
and PPTS readily proceeded and furnished intermediate
14 in 59% yield over two steps from 12 Scheme 5.
BnO
O
dil. HCl
OH
H
OTES
12
2
O
c) NaBH4
OH
O
OH
OH
d) DMP
PPTS
BnO
O
BnO
O
14
13
O
HO
Scheme 5. Synthesis of b-C-glycoside 2. Reagents and conditions: (a)
(i) AllylMgBr (3.0 equiv), Et2O, ꢀ78 °C, 2 h, 91%, (ii) TFA (6.0 equiv),
Et3SiH (6.0 equiv), CH2Cl2, ꢀ78 °C, 4 h, 59%. (b) O3, sudan III
indicator, ꢀ78 °C, CH2Cl2, 15 min, 95%. (c) NaBH4 (5.0 equiv),
MeOH, 0 °C, 4 h, 71%. (d) DMP (10.0 equiv), PPTS (0.2 equiv),
CH2Cl2, rt, 12 h, 83%. DMP = 2,2-dimethoxypropane; PPTS = pyrid-
inium p-toluenesulfonate.
Acknowledgments
Support was provided by the University of Alabama
and the NSF (CHE-0115760) for the departmental
NMR facility.
In conclusion, we have completed an efficient synthesis
of the C17–C25 subunit resident in (ꢀ)-lasonolide A.
The key reaction features that were utilized include a
Tsuchihashi–Yamamoto type rearrangement and
Molander–Reformatsky SmI2 mediated intramolecular
aldol reaction sequence. Lastly, a diastereoselective
target oriented b-C-glycoside formation sequence via
an axial oxocarbenium reduction completed the stereo-
chemistry required for the completion of the C17–C25
segment of (ꢀ)-lasonolide A. Studies toward the total
synthesis of 1 are ongoing and will be reported in due
course.
References and notes
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H
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Figure 1. Key NOE enhancements of intermediate 2.

5180
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15. Data for b-hydroxy aldehyde 4: 1H NMR (360 MHz,
CDCl3) d 9.49 (s, 1H), 7.36 (m, 5H), 5.77 (dd, J = 10.9, 6.8,
1H), 5.39 (d, J = 11.6, 1H), 5.21 (d, J = 17.5, 1H), 4.55 (s,
2H), 4.26 (dd, J = 4.5, 3.9, 1H), 3.75 (m, 2H), 3.33 (br s,
1H), 1.73 (m, 2H), 1.26 (s, 3H). 13C NMR (125 MHz,
CDCl3) d 202.6, 137.8, 136, 128.5, 127.8, 127.7, 118.4, 73.4,
69.2, 57.8, 30.8, 12.2. IR (neat): 3480, 2865, 1728, 1454,
1367, 1250, 1093, 931, 742 cmꢀ1. Rf at 10% EtOAc in
6. White, J. D.; Blakemore, P. R.; Browder, C. C.; Hong, J.;
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25
hexanes: 0.32. ½aꢁD ꢀ38.31 (c 0.014, CHCl3). HRMS (EI)
8. Horton, P. A.; Koehn, F. E.; Longley, R. E.; McConnell,
O. J. J. Am. Chem. Soc. 1994, 116, 6015.
Calcd for C15H20O3 (M+): 248.1412, found: 248.1410.
16. Data for lactone 3: 1H NMR (360 MHz, CDCl3) d 7.33 (m,
5H), 5.85 (dd, J = 11.1, 6.6, 1H), 5.32 (dd, J = 17.9, 11.6,
1H), 4.95 (dd, J = 8.9, 1.6, 1H), 4.52 (d, J = 6.1, 1H), 3.7
(m, 3H), 2.88 (dd, J = 13.9, 4.8, 1H), 2.66 (dd, J = 16.4,
2.3, 1H), 1.85 (m, 1H), 1.74 (m, 1H), 1 (s, 3H). 13C NMR
(125 MHz, CDCl3) d 139.7, 138.1, 128.4, 127.7, 127.6,
117.1, 73.2, 71.6, 66.6, 42.3, 35.8, 30.6, 15.1. IR (neat):
3445, 3014, 2977, 2934, 2870, 1724, 1380, 1237, 1213, 1102,
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25
1074, 758 cmꢀ1. Rf at 60% EtOAc in hexanes: 0.35. ½aꢁD
(M+): 290.1518, found: 290.1510.
ꢀ58.23 (c 0.005, CHCl3). HRMS (EI) Calcd for C17H22O4
17. We have utilized the Molander–Reformatsky intramole-
cular aldol reaction during the synthesis of both diospon-
gins A and B and the partial synthesis of (ꢀ)-lasonolide A.
Our observed modest to good yields of 51–55% (Refs. 7d
and 9k) are consistent with the reported values by
Molander as described in Ref. 11.
1
18. Data for b-C-glycoside 2: H NMR (360 MHz, CDCl3) d
7.33 (m, 5H), 5.82 (m, 2H), 5.26 (d, J = 11.0, 1H), 5.17 (d,
J = 18.0, 1H), 5.04 (dd, J = 17.0, 8.8, 2H), 4.5 (dd,
J = 20.5, 12.0, 2H), 3.96 (d, J = 9.5, 1H), 3.79 (m, 1H),
3.6 (m, 3H), 2.27 (m, 1H), 2.15 (m, 1H), 1.73 (m, 1H), 1.65
(m, 2H), 1.03 (s, 3H), 0.98 (t, J = 7.6, 9H), 0.61 (q, J = 7.6,
6H). 13C NMR (125 MHz, CDCl3) d 142.8, 135.3, 128.6,
127.8, 127.7, 116.6, 116.5, 108.8, 73.6, 73.6, 73.2, 71.5, 68,
43.7, 40.6, 34.4, 31, 16.8. IR (CDCl3): 3422, 2935, 2887,
2372, 1727, 1419, 1069 cmꢀ1. Rf at 20% EtOAc in hexanes:
25
11. Molander, G. A.; Etter, J. B.; Harring, L. S.; Thorel, P. J.
J. Am. Chem. Soc. 1991, 113, 8036.
0.35. ½aꢁD ꢀ6.2 (c 0.04, CHCl3). HRMS (EI) Calcd for
C20H28O3 (M+): 316.2038, found: 316.2038.