Synthetic studies on amphidinolide B1

Article abstract of DOI:10.1021/ol052620g

The syntheses of three fragments, 2, 3, and 4, of amphidinolide B1 have been accomplished. The 1,3-isomerization of allylic alcohol 10 was accomplished via rhenium oxo catalysis and has been applied successfully in the synthesis. (-)-MIB-catalyzed asymmetric vinylzinc addition to aldehyde 31 and the regio- and stereoselective epoxidation of unsymmetrical divinyl methanol 32 were key steps.

Full text of DOI:10.1021/ol052620g

ORGANIC
LETTERS
2006
Vol. 8, No. 3
427-430
Synthetic Studies on Amphidinolide B1
Amit K. Mandal,† John S. Schneekloth, Jr.,‡ Kouji Kuramochi,† and
Craig M. Crews*,‡,†,§
Departments of Chemistry, Molecular, Cellular, and DeVelopmental Biology, and
Pharmacology, Yale UniVersity, New HaVen, Connecticut 06520-8103
craig.crews@yale.edu
Received October 28, 2005
ABSTRACT
The syntheses of three fragments, 2, 3, and 4, of amphidinolide B1 have been accomplished. The 1,3-isomerization of allylic alcohol 10 was
accomplished via rhenium oxo catalysis and has been applied successfully in the synthesis. ( )-MIB-catalyzed asymmetric vinylzinc addition
to aldehyde 31 and the regio- and stereoselective epoxidation of unsymmetrical divinyl methanol 32 were key steps.
−
Amphidinolide B1 (1), a polyketide-based 26-membered
macrolide, was isolated from a culture of the symbiotic
marine dinoflagellate Amphidinium sp. (strain Y-5) in 1987
by Kobayashi et al.1,2 There have been several reports of
partial syntheses toward 1; however, no completed total
synthesis has been disclosed yet.3
difficult than C-O bond-forming reactions, we hope that
this new strategy will increase the efficiency of the synthesis.
The synthesis of fragment 2 began with Brown’s crotyla-
tion reaction (Scheme 2).7 The reaction of trans-crotonal-
dehyde and (E)-crotyldiisopinocamphenylborane (prepared
from trans-butene, n-BuLi, t-BuOK, and (+)-Ipc2BOMe) in
In our laboratory, we undertook a multipronged approach
toward the synthesis of amphidinolide B1 (1) (Scheme 1).
One strategy was communicated earlier,4 whereas this paper
represents an alternative strategy. Our previous strategy
involved three major C-C bond-forming reactions and one
C-O bond-forming reaction. This new retrosynthetic analysis
involves two C-C and one C-O bond-forming coupling
reactions: Suzuki-Miyaura coupling,5 an aldol reaction,6 and
macrolactonization using the three fragments 2, 3, and 4.
As C-C bond-forming reactions are traditionally more
Scheme 1
† Department of Molecular, Cellular, and Developmental Biology.
‡ Department of Chemistry.
§ Department of Pharmacology.
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T.; Hirata, Y.; Sasaki, T.; Ohta, T.; Nozoe, S. J. Nat. Prod. 1989, 52, 1036.
10.1021/ol052620g CCC: $33.50
© 2006 American Chemical Society
Published on Web 01/06/2006

Scheme 2
the presence of BF3‚OEt2 in THF-Et2O at -78 °C produced
of the allylic TBS ether furnished 10 in 70% yield over two
steps. At this point, the stage was set to manipulate allylic
alcohol 10 to the requisite R,â-unsaturated ketone 12 and to
install the remaining stereogenic centers. The 1,3-isomer-
ization of 10 and subsequent oxidation promised to be an
the allyl alcohol 6 in 50% yield and 14:1 anti/syn selectivity.
Silyl protection of the hydroxyl group and a regioselective
hydroboration-oxidation sequence furnished alcohol 7,
which was oxidized to the corresponding aldehyde 8 using
Dess-Martin periodinane. The asymmetric methylation of
8 with Me2Zn and Ti(OiPr)4 was examined with the chiral
ligands BINOL and bissulfonamide.8 Unfortunately, the
conversions were unacceptable in both cases (25% and 29%,
respectively). However, diastereoselective methylation to
obtain 9 was achieved with Seebach’s method9 [Me2Zn and
Ti(OiPr)4 in the presence of (-)-TADDOL] in 92% yield
10
atom-efficient method to access ketone 12. Ph3SiOReO3
is currently the most effective catalyst for 1,3-isomerization.11
When we treated 10 in the presence of 1 mol % catalyst in
ether at -60 °C, complete isomerization to regioisomeric
allylic alcohol 11 was observed in 5 min. Oxidation of the
alcohol 11 under Dess-Martin periodinane conditions
furnished the R,â-unsaturated ketone 12. Swapping TIPS
protection with TBS, Sharpless asymmetric dihydroxylation12
followed by acetonide formation completed the synthesis of
fragment 2.
1
and a 5-7:1 diastereomeric ratio (based on H NMR).
Protection of the free alcohol as a TIPS ether (the minor
isomer can be separated at this stage) and selective cleavage
The synthesis of fragment 3 started with known vinyl
iodide 1313 (Scheme 3). Transmetalation with t-BuLi in Et2O
and capture of the resulting vinyllithium species with
acetaldehyde yielded (()-allylic alcohol 14. Sharpless kinetic
resolution14 of (()-14 gave the desired epoxide 15 in 85-
90% enantiomeric excess (ee) and unreacted alcohol in 25-
30% ee as a mixture that proved difficult to separate. The
crude mixture was subjected to a Parikh-Doering oxidation
to yield easily separable epoxy ketone 16 and the corre-
sponding R,â-unsaturated ketone (not shown). The R,â-
unsaturated ketone was subjected to a Luche reduction to
produce (()-allylic alcohol 14, which was recycled under
Sharpless kinetic resolution conditions. The Horner-Wads-
worth-Emmons condensation of epoxy ketone 16 with
phosphonate in the presence of NaHMDS produced enyne
17 [82% yield, E/Z ) 6:1]. Simultaneous cleavage of TBS
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Soc. 1998, 75, 741. (l) Chakraborty, T. K.; Suresh, V. R.; Vayalakkada, R.
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428
Org. Lett., Vol. 8, No. 3, 2006

Scheme 3
Scheme 4
form the C12-C13 bond successfully using the (B)-alkyl
Suzuki-Miyaura coupling reaction between (B)-alkylborane
(derived from regioselective hydroboration of fragment 4)
and (()-1,3-vinyl iodide fragment 3 (synthesis not shown)
to put together the C1-C18 portion of the molecule.
However, investigations revealed that 1,3-stereocontrol can-
not be achieved with this substrate, as hydroboration of
fragment 4 with 9-BBN provided a 1:1 inseparable mixture
of diastereoisomers at C11 (amphidinolide B1 numbering).
Considering A values, an alkyl group (i.e., Me ) 1.74
kcal/mol) imparts more nonbonding interaction than an
OSiR3 group (i.e., OSiMe3 ) 0.74 kcal/mol), presumably
because the SiR3 group can be turned away to avoid the steric
interaction.18 This explains the loss of π-facial selectivity in
our substrate. As separation of the diastereoisomers was not
easy, we revised our strategy and decided to use compound
25 as a new fragment for the C1-C12 segment in which
the C11 methyl stereogenic center is preinstalled (Scheme
5). Instead of coupling the 1,3-diene iodide fragment 3 to
ether and the TMS group by TBAF followed by regioselec-
tive opening of the epoxide in the presence of LiAlH4 in
Et2O furnished diol 18, which was separated from the minor
(Z) isomer using column chromatography. Functionalization
of the enyne 18 to the 1,3-diene iodide was quite problematic.
After exploring several possibilities, we found that the triple
bond could be silylstannylated regio- and stereoselectively
employing n-Bu3SnSiMe2Ph/Pd(PPh3)4 to produce function-
alized diene 19.15 TBAF-mediated removal of the PhMe2Si
group produced stannane 20. Reaction with I2 and selective
TBS protection completed the synthesis of fragment 3.
The synthesis of fragment 4 began with aldehyde 21
(Scheme 4). A nonchelation-controlled SE2′ reaction between
aldehyde 21 and methallylsilane in the presence of BF3‚OEt2
furnished homoallylic alcohol 22 in 90% yield and g95:5
diastereomeric ratio (dr).16 Hydroxyl group protection as a
TBS ether 23, followed by oxidative deprotection of the PMB
ether, revealed the primary alcohol. The alcohol was then
converted to the aldehyde, which was subjected to vinyl-
magnesium bromide addition to provide allyl alcohol 24 as
Scheme 5
1
a 1.5:1 diastereomeric mixture (based on H NMR). The
allylic alcohol 24 underwent Johnson ortho ester Claisen
rearrangement to provide the homologated ethyl ester
exclusively as the (E) isomer. Reduction to the aldehyde
using i-Bu2AlH in THF and the Wittig reaction furnished
fragment 4 with exclusive (E) selectivity.
With all three fragments securely in hand, we sought to
explore the possibility of setting up the C11 stereogenic
centers by hydroboration and a subsequent (B)-alkyl Suzuki-
Miyaura coupling reaction5 to assemble the 1,3-diene. We
hoped to induce 1,3-stereocontrol on the basis of Evans’
alkyl-directed hydroboration model.17 We have been able to
(B)-alkylborane (derived by hydroboration from fragment 4),
we decided to couple it to the ate complex 26 derived from
(15) (a) Mitchell, T. N.; Wickenkamp, R.; Amamria, A.; Dieke, R.;
Scheider, U. J. Org. Chem. 1987, 52, 4868. (b) Chenard, B. L.; Van Zyl,
C. M. J. Org. Chem. 1986, 51, 3561.
(17) Evans, D. A.; Bartroli, J.; Godel, T. Tetrahedron Lett. 1982, 23,
4577.
(18) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic
Compounds; John Wiley & Sons: New York, 1993; p 696.
(16) Reetz, M. T.; Kesseler, K. J. Org. Chem. 1985, 50, 5434.
Org. Lett., Vol. 8, No. 3, 2006
429

the corresponding iodide easily accessible from compound
25 in two steps.19 Preliminary studies involving (()-
alkenyliodide fragment 3 and a model alkyl boronate to
assemble the 1,3-diene corroborate the feasibility of this
strategy.20
metalation at 0 °C, as described in the literature,23 led to
decomposition of the substrate. After extensive experimen-
tation, we found that the reaction could be performed
successfully by adding Me2Zn followed by (-)-MIB at
-78 °C to alkenylborane. The mixture was then warmed to
-20 °C over 10 min. The aldehyde 31 in hexane was added
via syringe pump over 20 min while warming the mixture
to 0 °C to furnish divinyl methanol 32 in 43% yield and
g95% diastereomeric excess (de). This assembled the full
carbon backbone of compound 25. The next challenge was
to functionalize stereoselectively the C7-C8 double bond
of this unsymmetrical divinyl methanol 32.
The synthesis of compound 25 commenced with isoprene
monoxide (Scheme 6). TiCl4-mediated regioselective and
Scheme 6
It is documented that the simple (()-unsymmetrical divinyl
methanols can be subjected to the Sharpless kinetic resolution
conditions to synthesize the optically active monoepoxide.24
However, to the best of our knowledge, Sharpless asymmetric
epoxidation has not been applied to desymmetrize a complex
unsymmetrical divinyl methanol such as ours in the context
of natural product synthesis. We were pleased to find that
Sharpless’ asymmetric epoxidation provided the C7-C8
monoepoxide in 71% yield (6:1 dr). TIPS protection went
uneventfully to furnish 25 in 90% yield.
In conclusion, we have accomplished the synthesis of three
fragments, 2, 3 and, 4. Compound 25 will be used as the
new fragment for the C1-C12 segment. 1,3-Isomerization
of allylic alcohol via rhenium oxo catalysis has been applied
successfully in our synthesis. (-)-MIB-catalyzed asymmetric
vinylzinc addition to aldehyde 31, highly selective late-stage
epoxidation of divinyl methanol 32, and regio- and stereo-
selective silylstannylation to synthesize stannane 20 have
been used as key steps. Continued advancement of these
intermediates toward the eventual total synthesis of 1 are
currently ongoing in our laboratory.
stereoselective opening of the epoxide provided the alcohol,
which was protected as a TIPS ether 28. It was then coupled
with propargylmagnesium bromide in the presence of Pd-
(PPh3)4 to give acetylene 29 in 83% yield. In parallel,
aldehyde 31 was synthesized in two steps via the Wittig
reaction, followed by reduction with i-Bu2AlH. The key
strategy is to employ asymmetric addition of alkenylzinc to
aldehyde 31 in the presence of Nugent’s21 isoborneol-based
(-)-MIB ligand.22 Hydroboration of the terminal acetylene
29 with freshly prepared dicyclohexylborane proceeds regio-
selectively to afford the alkenylborane. Transmetalation of
this alkenylborane with Me2Zn generates the reactive al-
kenylzinc reagent in situ. Attempts to carry out the trans-
Acknowledgment. We gratefully acknowledge financial
support from NIH (GM062120). J.S.S. acknowledges the
American Chemical Society, Division of Medicinal Chem-
istry, and Aventis Pharmaceuticals for a pre-doctoral fel-
lowship.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL052620G
(19) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(20) Unpublished results.
(21) Nugent, W. A. J. Chem. Commun. 1999, 1369.
(22) (a) Oppolzer, W.; Radinov, R. N. HelV. Chim. Acta 1992, 75, 170.
(b) Review: Pu, L.; Yu, H.-B. Chem. ReV. 2001, 101, 757.
(23) Chen, Y. K.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2002,
124, 12225.
(24) Honda, T.; Mizutani, H.; Kanai, K. J. Chem. Soc., Perkin Trans. 1
1996, 14, 1729.
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