Diastereoselective formation of tetrahydrofurans via pd-catalyzed asymmetric allylic alkylation: Synthesis of the C13-C29 subunit of amphidinolide N

Article abstract of DOI:10.1021/ol302409g

An efficient synthesis of the C13-C29 fragment of amphidinolide N is described. The synthesis relies on a new strategy involving Pd-catalyzed asymmetric allylic alkylation to generate diastereoselectively the cis- or trans-THF unit simply by varying the enantiomer of the ligand. The C19 hydroxyl-bearing stereocenter was introduced using a chelation-controlled allylation which led exclusively to a single diastereoisomer.

Full text of DOI:10.1021/ol302409g

ORGANIC
LETTERS
2012
Vol. 14, No. 22
5632–5635
Diastereoselective Formation of
Tetrahydrofurans via Pd-Catalyzed
Asymmetric Allylic Alkylation: Synthesis of
the C13ÀC29 Subunit of Amphidinolide N
Barry M. Trost* and Jullien Rey
Department of Chemistry, Stanford University, Stanford, California 94305-5080,
United States
bmtrost@stanford.edu
Received August 30, 2012
ABSTRACT
An efficient synthesis of the C13ÀC29 fragment of amphidinolide N is described. The synthesis relies on a new strategy involving Pd-catalyzed
asymmetric allylic alkylation to generate diastereoselectively the cis- or trans-THF unit simply by varying the enantiomer of the ligand. The C19
hydroxyl-bearing stereocenter was introduced using a chelation-controlled allylation which led exclusively to a single diastereoisomer.
Amphidinolide N was isolated in 1994 from the marine
microorganism Amphidinium sp. and displayed highly
promising preliminary biological activity with high cyto-
toxicity in vitro against the murine lymphoma L1210
(IC50 = 0.08 nM) and the human epidermoid carcinoma
KB cell lines (IC50 = 0.09 nM).1 Kobayashi initially
reported a partial structure of amphidinolide N (1) con-
sisting of a 26-membered lactone, an allylic epoxy alcohol,
and a six-membered hemiacetal ring; the relative confi-
guration (C14, C15, C16, and C19) was assigned by NOE
experiment (Scheme 1). Soon after, Shimizu reported the
isolation of caribenolide I (2), a natural product whose
structure shared many structural similarities with 1, the
only difference being the hydration of the C21ÀC24 tetra-
hydrofuran (THF) ring.2 With the chemical structures of
the amphidinolide natural product family taken into
consideration,3 the possibility that 1 and 2 are isomeric
compounds has been suggested and a revised structure of
amphidinolide N (3), including a complete relative stereo-
chemical assignment, is postulated (Scheme 1).4
To date, no total synthesis of amphidinolide N has been
reported in the literature.5 In view of its biological activity
and unprecedented carbon framework, as well as its
limited availability from natural sources, and in order to
prove the structural proposition, we recently decided to
undertake a concise and convergent total synthesis of 3. A
common structural feature of some members of the am-
phidinolide family is the presence of an R-hydroxy-THF
motif (amphidinolides C, E, F, M, and U).3 As part of our
ongoing projects involving the development of new syn-
thetic methods using asymmetric metal catalysis, we ini-
tially focused on the synthesis of the C13ÀC29 fragment of
3 with a particular interest for the diastereoselective synthe-
sis of the challenging R-hydroxy trans-THF unit. From
a retrosynthetic point of view, it was proposed that 3 could
be disconnected into two fragments of equal complexity,
C1ÀC12 and C13ÀC29, which might be assembled by
means of our ruthenium catalyzed alkene/alkyne coupling6
and subsequent R-oxidation of the newly formed ketone
followed by macrolactonization (Scheme 2).
(5) For partial synthesis, see: (a) Nicolaou, K. C.; Brenzovich, W. E.;
Bulger, P. G.; Francis, T. M. Org. Biomol. Chem. 2006, 4, 2119–2157. (b)
Nicolaou, K. C.; Bulger, P. G.; Brenzovich, W. E. Org. Biomol. Chem.
2006, 4, 2158–2183.
(6) (a) Trost, B. M.; Toste, F. D. Tetrahedron Lett. 1999, 40, 7739–
7743. (b) Application in total synthesis: Trost, B. M.; Gunzner, J. L.
J. Am. Chem. Soc. 2001, 123, 9449–9450.
(1) Ishibashi, M.; Yamaguchi, N.; Sasaki, T.; Kobayashi, J. J. Chem.
Soc., Chem. Commun. 1994, 1455–1456.
(2) Bauer, I.; Maranda, L.; Young, K. A.; Shimizu, Y; Fairchild, C.;
Cornell, L.; MacBeth, J.; Huang, S. J. Org. Chem. 1995, 60, 1084–1086.
(3) Kobayashi, J. J. Antibiot. 2008, 5, 271–284.
(4) Kobayashi, J. Personal communication.
r
10.1021/ol302409g
Published on Web 10/25/2012
2012 American Chemical Society

Scheme 1. Revised Postulated Structure of Amphidinolide N (3)
Scheme 3. Synthesis of Redox-Isomerization Precursor 15
primary propargyl alcohol 15 was obtained by reaction of
14 with paraformaldehyde.
The redox isomerization of propargyl alcohol 15 was
then investigated (Table 1). When 15 was treated with
5 mol % of IndRu(PPh3)2Cl, 5 mol % of indium triflate,
and 30mol % of CSA in THF atreflux, the desiredcyclized
product was formed in excellent yield (Table 1, entry 1).12
It was initially thought that the chiral diol might induce
some degree of diastereoselectivity during the oxa-Michael
addition, but diastereomeric THF’s 17 and 18 were isolated
as an inseparable 1:1 mixture. Reducing the amount of acid
to 10 mol % or lowering the temperature of the reaction to
decrease the rate of cyclization led to either formation of the
cyclized product with no diastereocontrol or no reactivity at
rt (Table 1, entries 2À4). In all cases, no trace of the enal
intermediate 16 was detected by crude NMR of the reaction
mixture. Addition of L-proline to the reaction mixture to
generate an iminium species in situ and catalyze the dia-
stereoselective formation of the cis- or trans-THF only led
to unreacted starting material (probably because of catalyst
poisoning by the secondary amine) (Table 1, entry 5).
In view of these results, a revised strategy was clearly
needed to generate diastereoselectively the R-hydroxy
trans-THF unit. Accordingly, a new approach for the
diastereoselective formation of either 2,5-cis- or trans-
disubstituted THF rings was envisaged using chiral cata-
lysts in an unprecedented Pd-catalyzed asymmetric allylic
alkylation (Pd-AAA) reaction. Thus, differentiating
the gem-diacetates of 19 (Scheme 4) and directing the
regioselectivity of the nucleophilic attack to the distal
carbon were required.13
We report herein the highly diastereoselective synthesis
of the C13ÀC29 subunit 4 of amphidinolide N (3)
(Scheme 2). It was initially envisaged that the C19 hydroxy
group could be introduced by hydrosilylation of homo-
propargylic alcohol 5, followed by FlemingÀTamao oxi-
dation of the resulting vinylsiloxane and diastereoselective
ketone reduction. The homopropargylic alcohol5 could be
generated by epoxide opening of terminal alkyne 6. The
key step to install the challenging trans-THF 6 would rely
on a tandem redox isomerization/oxa-Michael addition
reaction. Finally, the precursor propargyl alcohol 7 could
be synthesized from allylic alcohol 8.
The synthesis started with the conversion of primary
allylic alcohol 8 to the corresponding allylic chloride 9
(Scheme 3).7 The trans-olefin was then subjected to Sharp-
less dihydroxylation conditions, leading to the known
diol 10,8 in excellent yield and enantioselectivity.9 The
latter was then treated with sodium hydroxide to form
epoxide 11 and converted to silyl ether 12. Our choice to
introduce a TBDPS ether was driven by our need to use
protecting groups stable under the redox isomerization
reaction conditions.10 Epoxide 12 was then opened using
allenylmagnesium bromide, generated in situ from propar-
gyl bromide (13) to form terminal alkyne 14.11 Finally,
Scheme 2. Retrosynthetic Analysis of Amphidinolide N (3)
Opening the previously synthesized epoxide 12 with
allylmagnesium bromide (21) led to terminal alkene 22
(Scheme 5).14 The latter was then engaged in a cross-
metathesis reaction with allyl gem-diacetate (20) to yield
the corresponding (E)-olefin 19 in good yield.15
(7) Snyder, E. I. J. Org. Chem. 1972, 37, 1466.
(8) Vanhessche, K. P. M.; Wang, Z.-M.; Sharpless, K. B. Tetrahedron
Lett. 1994, 35, 3469–3472.
(9) Ee determined on intermediate 12.
(10) Trost, B. M.; Livingston, R. C. J. Am. Chem. Soc. 2008, 130,
11970–11978.
(11) Nakayama, Y.; Kumar, B. G.; Kobayashi, Y. J. Org. Chem.
2000, 65, 707–715.
(12) Trost, B. M.; Gutierrez, A. C.; Livingston, R. C. Org. Lett. 2009,
11, 2539–2542.
(13) Trost, B. M. Org. Process Res. Dev. 2012, 16, 185–194.
Org. Lett., Vol. 14, No. 22, 2012
5633

Table 1. Tandem Redox Isomerization/Oxa-Michael Addition
Table 2. THF Cyclization via Pd-AAA Approach
yield
entry
conditions
(conversion)
comments
1:1 dr
yielda
drb
1
2
3
4
5
30% CSA, 66 °C
10% CSA, 66 °C
30% CSA, rt
74% (100%)
70% (100%)
(0%)
entry
conditions
L1 (S,S), rt, 0.15 M
(conversion) (23:24)
1:1 dr
1
2
3
4
5
6
7c
8
9
traces
À
SM recovered
1:1 dr
L1 (S,S), 50 °C, 0.15 M
L1 (R,R), 50 °C, 0.15 M
L1 (R,R), 35 °C, 0.15 M
L1 (R,R), 50 °C, Et3B, 0.15 M
L1 (R,R), 50 °C, Et2Zn, 0.15 M
L1 (R,R), 50 °C, Et3N, 0.15 M
L1 (R,R), 66 °C, Et3N, 0.15 M
75% (100%)
77% (100%)
(58%)
1:4
30% CSA, 40 °C
30% CSA, 20% L-Pro,
66 °C
(<10%)
4:1
traces
catalyst
poisoning
3.3:1
1.2:1
1:2
(100%)
(90%)
82% (100%)
(100%)
4.6:1
3.5:1
À
L1 (R,R), 50 °C, EtN(i-Pr)2, 0.15 M (<10%)
Scheme 4. Revised Strategy To Access the trans-THF 6
10d L1 (R,R), 50 °C, AcOH, 0.15 M
11
(100%)
(100%)
(100%)
3.6:1
3.7:1
4:1
L1 (R,R), 50 °C, Et3N, 0.4 M
L1 (R,R), 50 °C, Et3N, 0.05 M
12
a Isolated yield. b dr determined from the 1H NMR of the crude
mixture. c <5% formation of the undesired byproduct. d 30% formation
of the undesired byproduct.
Witholefin 19inhand, the Pd-AAAcyclization was then
investigated (Table 2). When olefin 19 was subjected to
5 mol % of Pd2(dba)3 CHCl3 and 15 mol % of (S,S)-Trost
the free hydroxy group to see whether a faster attack on
the π-allyl to prevent equilibration of the two diastereo-
meric π-allyl systems would influence the diastereo-
selectivity of the reaction. Additives such as Et3B18 or
Et2Zn19 failed to improve the selectivity of the reaction
(Table 2, entries 5À6).
3
standard ligand L1 at rt and under oxygen-free conditions,
only a trace amount of the cyclized product was observed.
At 50 °C, regioselective attack of the secondary alcohol on
the π-allyl intermediate led to the desired cyclized products
23 and 24 as a 1:4 mixture of diastereoisomers in 75% yield
(Table 2, entry 2). To determine their spatial relationship,
both isomers were successfully separated by flash column
chromatography and subjected to NOE experiments. Even
though a matched/mismatched case could have been an-
ticipated when using the (R,R)-L1 ligand, treatment of 19
with this ligand pleasingly afforded the desired trans-THF
23 as a 4:1 mixture of diastereoisomers, suggesting that the
observed selectivity was due to catalyst control (Table 2,
entry 3). In view of the observed stereochemistry, the
diastereodetermining stepappearstobethe intramolecular
nucleophilic attack on the π-allyl intermediate rather than
the ionization step.16 Using other ligands developed within
the Trost group either led to a drop of reactivity and/or
gave poor selectivity.17 We then envisioned activating
However, addition of 1.1 equiv of Et3N led to the
formation of an improved 4.6:1 mixture in favor of the
trans-THF in an excellent 82% yield (Table 2, entry 7). It is
believed that the improved yield and selectivity for this
transformation is due to the quenching of AcOH formed in
the reaction by the added base. In fact, when no base was
added (see entry 3), formation of around 10À15% of an
unidentified byproduct was observed in the crude NMR,20
while less than 5% was detected with addition of Et3N.
Formation of this byproduct is probably acid-catalyzed.
To validate this hypothesis, 1.1 equiv of AcOH was added
to the reaction mixture leading to both a drop of diastereo-
selectivity and an increase of the byproduct formation
(30% by the crude NMR) (Table 2, entry 10). The use
€
of the Hunig base surprisingly shut down the reaction
(14) Takahashi, S.; Ogawa, N.; Koshino, H.; Nakata, T. Org. Lett.
2005, 7, 2783–2786.
(15) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H.
J. Am. Chem. Soc. 2003, 125, 11360–11370.
(16) Trost, B. M.; Chulbom, L. J. Am. Chem. Soc. 2001, 123, 3671–
3686.
Scheme 5. Synthesis of the Pd-AAA Precursor 19
(17) Details are given in the Supporting Information.
(18) Trost, B. M.; McEachern, E.; Toste, F. D. J. Am. Chem. Soc.
1998, 120, 12702–12703.
(19) Kim, H.; Chulbom, L. Org. Lett. 2002, 4, 4369–4371.
(20) This byproduct could not be isolated in pure form and conse-
quently characterized.
5634
Org. Lett., Vol. 14, No. 22, 2012

Scheme 6. Hydrosilylation of Homopropargyl Alcohol 27
Scheme 7. Access to C13ÀC29 Fragment via Chelation Control
suggesting that the Et3N also plays a role in activating the
alcohol by hydrogen bonding (Table 2, entry 9). Working
on more diluted or concentrated conditions did not in-
crease the diastereoselectivity of the reaction (Table 2,
entries 11À12).
1,3-diols, we were intrigued to see how β-alkoxy aldehyde
17 would react under Keck conditions. Pleasingly, when 17
was treated with MgBr2 and allyltributyltin (30), alcohol
32 was obtained as a single diastereoisomer (Scheme 7).
It seems likely from the transition state 31 that the nucleo-
phile will attack the “re” face of the aldehyde to avoid any
axial interactions with the THF unit (a similar transition
state has been proposed by Keck26).
TIPS protection of the resulting secondary alcohol
followed by a hydroboration/oxidation sequence led to
aldehyde 34 in excellent yield (Scheme 7). Finally, Brown’s
alkoxyallylation27 provided the desired C13ÀC29 frag-
ment 36 in good yield and diastereoselectivity. It is worth
noting that the stereocenter C15 will be destroyed during
the alkene/alkyne coupling reaction to generate the corres-
ponding ketone.
In conclusion, we have reported the synthesis of the
C13ÀC29 fragment of amphidinolide N. Our initial strate-
gy based on our redox isomerization protocol did not show
any diastereocontrol during the oxa-Michael addition step.
The implementation of a new strategy based upon the
use of a Pd-AAA approach allowed access to either the
required trans-THF or the cis-isomer diastereoselectively
in a catalyst controlled reaction. A chelation-controlled
allylation allowed us to set efficiently the C19 stereogenic
center. Efforts are now underway to complete the total
synthesis of amphidinolide N.
Conversion of vinyl acetate 23 to the corresponding
aldehyde 17 to access the desired terminal alkyne was then
required (Scheme 6). Using K2CO3 in MeOH only led to
epimerization of the substrate (dr = 1:1). Under these
conditions, the rate of protonation of the in situ generated
enolate was slower than the rate of ring-opening leading to
epimerization. Fortunately, when Et3N was used, com-
plete conversion to the desired aldehyde 17 was observed.
Using the CoreyÀFuchs protocol,21 aldehyde 17 was then
converted to terminal alkyne 25 in excellent yield over two
steps.22 Alkyne 25 was reacted with the known epoxide
2623 to afford homopropargyl alcohol 27 in good yield.
Using our previously reported method for the hydro-
silylation of homopropargyl alcohols,24 27 was regio-
selectively converted to the intermediate six-membered
vinylsiloxane 28 via a two-step sequence (Scheme 6). Unfor-
tunately, despite many attempts to oxidize 28 using FlemingÀ
Tamao conditions, we were unable to successfully
form the desired ketone 29 and either no reaction (with
KHF2 and KF) or decomposition was observed (with
n-Bu4NF).25
At that point, we decided to revise our synthetic strategy
and introduce the C19 tertiary stereocenter earlier in
the synthesis. Keck showed that β-hydroxy aldehydes
could beconverted toanti-1,3-diolsusing chelation control
with various Lewis acids.26 Considering the fact that
hydroxyl-bearing stereocenters C19 and C21 of 3 are anti-
Acknowledgment. We thank the National Institutes of
Health for their generous support of our program (NIH
R01 GM-033049).
(21) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769–3772.
(22) One-step procedures using the BestmannÀOhira reagent led to
epimerization while the Colvin rearrangement gave decomposition.
Supporting Information Available. Experimental pro-
1
cedures and H and 13C NMR data for all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(23) Nicolaou, K. C.; Rodrıguez, R. M.; Mitchell, H. J.; Van Delft,
´
F. L. Angew. Chem., Int. Ed. 1998, 37, 1874–1876.
(24) Trost, B. M.; Ball, Z. T.; Laemmerhold, K. M. J. Am. Chem. Soc.
2005, 127, 10028–10038.
(25) (a) Fleming, I.; Barbero, A.; Walter, D. Chem. Rev. 1997, 97,
2063–2192. (b) Marshall, J. A.; Yanik, M. M. Org. Lett. 2000, 2, 2173–
2175.
(27) Brown, H. C.; Jadhav, P. K.; Bhat, K. S. J. Am. Chem. Soc. 1988,
110, 1535–1538.
(26) Keck, G. E.; Castellino, S.; Wiley, M. R. J. Org. Chem. 1986, 51,
5478–5480.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 22, 2012
5635