Fully reagent-controlled asymmetric synthesis of (-)-Spongidepsin via the Zr-catalyzed asymmetric carboalumination of alkenes (ZACA reaction)

Article abstract of DOI:10.1021/ol0707259

The ZACA reaction has been shown to proceed satisfactorily with internally OH-substituted 1-alkenes, provided that the OH group is unprotected and non-allylic. This reaction was used for reagent-controlled asymmetric construction of 3. Allylic alcohol was

Full text of DOI:10.1021/ol0707259

ORGANIC
LETTERS
2007
Vol. 9, No. 15
2771-2774
Fully Reagent-Controlled Asymmetric
Synthesis of ( )-Spongidepsin via the
−
Zr-Catalyzed Asymmetric
Carboalumination of Alkenes
(ZACA Reaction)
Gangguo Zhu and Ei-ichi Negishi*
Herbert C. Brown Laboratories of Chemistry, Purdue UniVersity, 560 OVal DriVe,
West Lafayette, Indiana 47907-2084
negishi@purdue.edu
Received March 24, 2007
ABSTRACT
The ZACA reaction has been shown to proceed satisfactorily with internally OH-substituted 1-alkenes, provided that the OH group is unprotected
and non-allylic. This reaction was used for reagent-controlled asymmetric construction of 3. Allylic alcohol was converted to 2 in seven steps
via iterative ZACA processes and simple chromatography. (
−)-Spongidepsin (1) was synthesized by using 2 and 3 through application of the
esterification amidation ring-closing metathesis protocol previously reported.
−
−
(-)-Spongidepsin (1), isolated from the Vanuatu marine
sponge Spongia sp., displays cytotoxic and antiproliferative
activities against J774.A1, HEK-293, and WEHI-164 cancer
cell lines,1 and its total syntheses and full stereochemical
assignments were reported by Forsyth2 and Ghosh3 in 2004.
More recently, Cossy4 reported a synthesis featuring a
diastereoselective crotylstannation of an R-chiral aldehyde,
followed by mesylation and reduction with LiAlH4. Our
interest in the synthesis of 1 primarily stemmed from an
excellent opportunity for demonstrating the high efficiency
in a fully reagent-controlled asymmetric construction of the
C1-C9 chiral fragment via recently developed Zr-catalyzed
asymmetric carboalumination of alkenes,5 ZACA reaction
hereafter, used in conjunction with simple and ordinary
chromatographic purification of 2,4-dimethyl-1-hydroxy-
butyl5e-i and 2-methyl-1,4-dihydroxybutyl derivatives.
Herein, we report efficient and fully reagent-controlled
asymmetric syntheses of the C1-C5 fragment (2) and the
C6-C13 fragment (3) via ZACA reaction and their applica-
tion to the synthesis of (-)-spongidepsin (1) by exploiting
the esterification-amidation-ring-closing metathesis6 strat-
(5) (a) Kondakov, D.; Negishi, E. J. Am. Chem. Soc. 1995, 117, 10771.
(b) Kondakov, D.; Negishi, E. J. Am. Chem. Soc. 1996, 118, 1577. (c) Huo,
S.; Negishi, E. Org. Lett. 2001, 3, 3253. (d) Huo, S.; Shi, J.; Negishi, E.
Angew. Chem., Int. Ed. 2002, 41, 2141. (e) Negishi, E.; Tan, Z.; Liang, B.;
Novak, T. Proc. Nat. Acad. Sci. U.S.A. 2004, 101, 5782. (f) Tan, Z.; Negishi,
E. Angew. Chem., Int. Ed. 2004, 43, 2911. (g) Magnin-Lachaux, M.; Tan,
Z.; Liang, B.; Negishi, E. Org. Lett. 2004, 6, 1425. (h) Novak, T.; Tan, Z.;
Liang, B.; Negishi, E. J. Am. Chem. Soc. 2005, 127, 2838. (i) Liang, B.;
Novak, T.; Tan, Z.; Negishi, E. J. Am. Chem. Soc. 2006, 128, 2770. (j)
Tan, Z.; Liang, B.; Huo, S.; Shi, J.; Negishi, E. Tetrahedron: Asymmetry
2006, 17, 512. (k) Huang, Z.; Tan, Z.; Novak, T.; Zhu, G.; Negishi, E.
AdV. Synth. Catal. 2007, 349, 539.
(1) Grassia, A.; Bruno, I.; Debitus, C.; Marzocco, S.; Pinto, A.; Gomez-
Paloma, L.; Riccio, R. Tetrahedron 2001, 57, 6257.
(2) Chen, J.; Forsyth, C. J. Angew. Chem., Int. Ed. 2004, 43, 2148.
(3) Ghosh, A. K.; Xu, X. Org. Lett. 2004, 6, 2055.
(4) Ferrie´, L.; Reymond, S.; Capdevielle, P.; Cossy, J. Org. Lett. 2006,
8, 3441.
10.1021/ol0707259 CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/21/2007

egy employed in all three previous syntheses2-4 (Scheme
1). The detailed schemes for the syntheses of the two key
Scheme 3
Scheme 1
intermediates 2 and 3 are presented in Schemes 2 and 3,
respectively. The synthesis of 2 was achieved via the
Scheme 2
overall yield via Brown allylboration7 to give 8 in 87% yield
(74% over three steps) and ZACA reaction of 8 to give, after
oxidation with O2, 9 (dr ) 3.5/1) in 73% yield (43% after
chromatographic purification to dr ) 40/1). Oxidation of 9
with PhI(OAc)2 (BAIB) and TEMPO gave 10 in 88% yield,
which was then reduced with DIBAL-H and olefinated by
the Wittig reaction to give 3 in 73% yield (two steps). Thus,
3 was obtained in 20% yield from 1,5-pentanediol over seven
steps (Scheme 3). In the Forsyth synthesis, a deliberate
stereodivergent construction of the C7 asymmetric center was
employed for the establishment of its stereochemistry,2 while
a substrate-controlled diastereoselective construction of the
C7 or C9 asymmetric center requiring later Mitsunobu
esterification8 with inversion was used by Ghosh3 and Cossy.4
As elegant as these syntheses are, use of the stoichiometric
quantitives of rather expensive chiral intermediates left some
room for improvement.
We initially opted for the construction of >97% pure 11
as a potential intermediate for the synthesis of 1 and prepared
it in a mere five steps from TBDPS-protected 3-buten-1-ol,
one lipase-catalyzed acetylation, and one chromatographic
purification, as recently reported5k (Scheme 4). As efficient
as this synthesis was, it did not deal with a critically required
construction of the C9 asymmetric center. Although the
ZACA reaction of proximally oxygenated 1-alkenes, such
as the parent allyl alcohol5i and homoallyl alcohol,5e had been
successfully developed, the corresponding reactions of the
internally oxygenated derivatives remained to be developed.
We therefore prepared several racemic ω-vinyl secondary
alcohols and their derivatives, such as 12-15, and examined
their ZACA reaction. To our disappointment, neither an
allylic alcohol (12a) nor its TBDPS-protected derivative
(12b) gave the desired ZACA product in more than 2% yield.
previously reported two-step conversion of allyl alcohol into
4 via 5 in 81% yield and 82% ee,5i followed by a one-pot
ZACA-oxidation tandem process and chromatographic
purification5f to give 6 in 24% overall yield (dr g 40/1) from
allyl alcohol (Scheme 2). Compound 6 was converted to 7
via Swern oxidation and Wittig olefination in 80% yield over
two steps, and 7 was then converted to 2 via desilylation
with TBAF, followed by PDC oxidation in 72% yield over
two steps (18% over seven steps).
The most distinguishing feature of this synthesis is the
efficient and reagent-controlled asymmetric construction of
3 in seven steps from inexpensive 1,5-pentanediol in 20%
(6) (a) Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1992, 114, 5426. (b)
Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446. (c)
Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (d) Scholl, M.; Ding,
S.; Lee, C.; Grubbs, R. H. Org. Lett. 1999, 1, 953. (e) Trnka, T. M.; Grubbs,
R. H. Acc. Chem. Res. 2001, 34, 18. (f) Fu¨rstner, A. Angew. Chem., Int.
Ed. 2000, 39, 3012.
(7) (a) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105, 2092.
(b) Ramachandran, P. V.; Reddy, M. V. R.; Brown, H. C. Pure Appl. Chem.
2003, 75, 1263.
(8) (a) Mitsunobu, O.; Yamada. M. Bull. Chem. Soc. Jpn. 1967, 40, 2380.
(b) Mitsunobu, O. Synthesis 1981, 1.
2772
Org. Lett., Vol. 9, No. 15, 2007

Scheme 4
Scheme 5
Similarly, a TBDPS-protected homoallyl alcohol (13b) failed
to undergo the ZACA reaction. Fortunately, however, the
parent alcohol (13a) gave the desired diol (16) in 75% yield.
The results obtained with 13a and 13b provide yet another
set of examples of the Zr-catalyzed carboalumination, which
demonstrates the desirability of using unprotected alcohols
along with the use of one additional equivalent of Me3Al5i
rather than their O-protetcted derivatives. The ZACA reaction
9
of (2S)-5-hexen-2-ol (14) with (-)- and (+)-Zr(NMI)2Cl2
as a catalyst provided the desired products 17a and 17b in
78-79% yields. The diastereomeric ratio of 7.7/1 observed
with (-)-Zr(NMI)2Cl2 is significantly higher than 4.5/1
observed with (+)-Zr(NMI)2Cl2. That the sense of asym-
metric induction is the same as in the ZACA reaction of
1-hexene has been confirmed by converting the (2R,5S)-
isomer (17a) into (2R)-2-methyl-1-hexanol by selective
protection of the terminal hydroxyl group with TBDPSCl,
mesylation of the other hydroxy group, reduction with
LiAlH4, and deprotection with TBAF, which yielded (2R)-
2-methyl-1-hexanol (77% ee) exhibiting the identical be-
mixture was warmed to 23 °C and stirred for 1 h to generate
the Me2Al-protected alkenol. In a separate reactor, 1.5 mL
(15 mmol) of Me3Al in 5 mL of CH2Cl2 was treated with
90 uL (5 mmol) of H2O to partially convert Me3Al to
methylaluminoxane (MAO).10 To this was added 167 mg
(0.25 mmol) of (+)-(NMI)2ZrCl2. To a wine-red solution
thus formed was added the Me2Al-protected alkenol solution
in CH2Cl2, and the resultant mixture was stirred overnight
at 23 °C. After the total consumption of the starting alkenol
was confirmed by GC, the mixture was treated at 0 °C with
a balloon full of O2 (about 3 L or 120 mmol) for 1-2 h and
then overnight at 23 °C under constant stirring. It was
quenched with 2 N NaOH, extracted with CH2Cl2, washed
with saturated aqueous NH4Cl and brine, dried over MgSO4,
and concentrated. After passing it through a short path
column of silica gel using EtOAc as an eluent to remove
metal-containing impurities, evaporation provided 1.51 g
(73%) of the crude product, which essentially consisted of
the desired product and its diastereoisomers (dr ) 3.5/1).
Purification by column chromatography (silica gel, 95/5-
85/15 hexanes-EtOAc) provided 872 mg (42%) of the
1
havior in analyses of H NMR spectra as that displayed by
the product obtained from 1-hexene with (-)-Zr(NMI)2Cl2
as the catalyst. These exploratory results are summarized in
Scheme 5.
Having established that the ZACA reaction of internally
hydroxylated 1-alkenes can proceed satisfactorily, as long
as the OH group is unprotected and non-allylic, we then
applied it to the synthesis of 3, as shown in detail in Scheme
3. Although not used in our eventual synthesis of 1, 15
having one less CH2 group was also prepared and subjected
to the ZACA reaction to produce 18a and 18b, as shown in
eq 5 of Scheme 5.
desired product (dr ) 40/1, by 13C NMR); [R]23 ) -7.5
D
(c, 2.1, CHCl3).
The final assemblage of (-)-spongidepsin (1) summarized
in Scheme 6 followed closely the strategy developed and
demonstrated first by Ghosh3 and employed recently by
Cossy.4 The final seven steps achieved in 54% overall yield
for the conversion of 19 into 1 confirm this part of the
synthesis to be efficient and satisfactory, and the spectral
The following procedure for the conversion of 8 into 9 is
representative of the ZACA reaction of internally hydroxy-
lated 1-alkenes. The starting alkenol (8) (1.91 g, 5 mmol)
dissolved in 5 mL of CH2Cl2 was mixed with 1.0 mL (10
mmol) of Me3Al in 5 mL of CH2Cl2 at -78 °C, and the
(9) Erker, G.; Aulbach, M.; Knichmeier, M.; Wingbermu¨ehle, D.;
Kru¨eger, C.; Nolter, M.; Werner, S. J. Am. Chem. Soc. 1993, 115, 4590.
(10) Wipf, P.; Ribe, S. Org. Lett. 2000, 2, 1713.
Org. Lett., Vol. 9, No. 15, 2007
2773

substituted 1-alkenes, in which the OH group is unprotected
and non-allylic. Although the extent of asymmetric induction
is affected to some extent by the proximal hydroxy-bearing
asymmetric carbon center, the reaction is nevertheless
reagent-controlled in that the chirality of the newly generated
asymmetric carbon center has so far been reliably predictable
from the chirality of Zr(NMI)2Cl2, namely the use of (+)-
and (-)-Zr(NMI)2Cl2 as catalysts leading to the formation
of (S)- and (R)-2-methyl-1-alkylalanes, respectively. This
development permits an efficient and fully reagent-controlled
asymmetric construction of the C6-C13 fragment of (-)-
spongidepsin (1), which has not previously been achieved.
Together with the previously developed ZACA route to
deoxypolypropionates5e-i applied to the efficient and selective
synthesis of the C1-C5 fragment (2), all three Me-branched
asymmetric carbon centers were constructed in a catalytic
and enantioface-selective manner through application of the
ZACA reaction. Although 5-epi-3 was used in two previous
syntheses of 1,3,4 3 was not. So, its applicability to the
synthesis of 1 was demonstrated by mostly following the
synthetic strategy previously established by other groups.2-4
Scheme 6
The ZACA reaction of 1-alken-3-ols, except for the case
of the parent allyl alcohol,5i still remains to be developed
and is highly desirable. In a more general vein, this study
has once again pointed to the desirability of further improving
the enantioselectivity of the ZACA reaction. At the current
level of enantioselectivity, the ZACA reaction in some cases
is limiting the yields of pure chiral products even though
the ZACA-based methodology is fundamentally efficient,
reasonably general, and potentially economical. Efforts along
this line are currently in progress.
data of 1 thus prepared are in full agreement with those
reported previously.4 The difference between this and the
previous syntheses lies in the esterification of N-Boc-
protected N-methylphenylalanine (20) with 3 to produce 19
employed in this study. The 89% yield observed for this
conversion compares favorably with the Mitsunobu esteri-
fication proceeding in about 70% yield employed in the
previous syntheses, which, in turn, was dictated by the use
of 5-epi-3 prepared via substrate-controlled diastereoselective
construction of one or the other asymmetric carbon center.3,4
In summary, this work has established that the ZACA
reaction5 is satisfactorily applicable to internally hydroxy-
Acknowledgment. We thank the National Institutes of
Health (GM 36792), the National Science Foundation (CHE-
0309613), and Purdue University for support of this research.
We also thank Professor Arun K. Ghosh (Purdue University)
for helpful discussions.
Supporting Information Available: Experimental pro-
1
cedures and H and 13C NMR spectra for compounds 1-3,
8-10, and 17-23. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL0707259
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Org. Lett., Vol. 9, No. 15, 2007