Total syntheses of amphidinolides T1 and T4 via catalytic, stereoselective, reductive macrocyclizations

Article abstract of DOI:10.1021/ja042733f

Described in this work are total syntheses of amphidinolides T1 and T4 using two nickel-catalyzed reductive coupling reactions of alkynes, with an epoxide in one case (intermolecular) and with an aldehyde in another (intramolecular). The latter was used t

Full text of DOI:10.1021/ja042733f

Published on Web 02/25/2005
Total Syntheses of Amphidinolides T1 and T4 via Catalytic,
Stereoselective, Reductive Macrocyclizations
Elizabeth A. Colby, Karen C. O’Brien, and Timothy F. Jamison*
Contribution from the Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
Received December 2, 2004; E-mail: tfj@mit.edu
Abstract: Described in this work are total syntheses of amphidinolides T1 and T4 using two nickel-catalyzed
reductive coupling reactions of alkynes, with an epoxide in one case (intermolecular) and with an aldehyde
in another (intramolecular). The latter was used to effect a macrocyclization, form a C-C bond, and install
a stereogenic center with >10:1 selectivity in both natural product syntheses. Alternative approaches in
which intermolecular alkyne-aldehyde reductive coupling reactions would serve to join key fragments were
investigated and are also discussed; it was found that macrocyclization (i.e. intramolecular alkyne-aldehyde
coupling) was superior in several respects (diastereoselectivity, yield, and length of syntheses). Alkyne-
epoxide reductive couplings were instrumental in the construction of key fragments corresponding to
approximately half of the molecule of both natural products. In one case (T4 series), the alkyne-epoxide
coupling exhibited very high site selectivity in a coupling of a diyne. A model for the stereoselectivity observed
in the macrocyclizations is also proposed.
garnered significant attention since its discovery in 2000.3
Introduction
Members of this subclass, amphidinolides T1-5 (1-5), contain
The amphidinolide family of marine macrolide natural
products has attracted a great deal of interest due to the potent
cellular effects and structural diversity displayed by its mem-
bers.1 Several amphidinolides exhibit extremely potent cyto-
toxicity against murine lymphoma L1210 cells as well as human
epidermoid carcinoma KB cells. To date, numerous subsets of
amphidinolides have been identified (A-Y), each of which
features a highly oxygenated macrolactone of varying ring sizes.
Since the first reports of the amphidinolide family, considerable
effort has been focused on synthesizing these macrolides,
resulting in several innovative and efficient total syntheses.2
a 19-membered macrocycle, a trisubstituted tetrahydrofuran
moiety, R-hydroxy ketone, an exocyclic methylene group, and
a homoallylic ester linkage. T3-T5 are the most closely related
molecules, all containing a ketone at C13, hydroxyl group at
C12, and methyl group at C14, and they differ only in their
configuration at C12 and C14. Amphidinolide T2 (2) displays
the same functionality at C12-C14 as 3-5, but contains an
additional hydroxymethyl substituent at C18 where the other
four members have an n-propyl group. Amphidinolide T1 (1)
differs from 3-5 in the oxidation states at C12 and C13,
possessing the reversed hydroxy ketone moeity.
Total syntheses of 1 and 3-5 have been reported to date.
Amphidinolide T4 was synthesized in 2002 by Fu¨rstner and
co-workers by taking advantage of an efficient ring-closing
metathesis to form the macrocycle.2k Related strategies were
applied by the same group to the syntheses of T1, T3, and T5
reported in 2003.2l Amphidinolide T1 was first synthesized by
Ghosh and Liu in 2003, utilizing a macrolactonization reaction
to form the 19-membered ring.2j
In particular, the amphidinolide T class (Figure 1) has
(1) For recent reviews of the amphidinolides, see: (a) Kobayashi, J.; Tsuda,
M. Nat. Prod. Rep. 2004, 21, 77-93. (b) Chakraborty, T. K.; Das, S. Curr.
Med. Chem.: Anti-Cancer Agents 2001, 1, 131-149. (c) Kobayashi, J.;
Ishibashi, M. In ComprehensiVe Natural Products Chemistry; Mori, K.,
Ed.; Elsevier: New York, 1999; Vol. 8, pp 619-649.
(2) Proposed structure of A: (a) Lam, H. W.; Pattendon, G. Angew. Chem.,
Int. Ed. 2002, 41, 508-511. (b) Maleczka, R. E., Jr.; Terrell, L. R.; Geng,
F.; Ward, J. S., III Org. Lett. 2002, 4, 2841-2844. (c) Trost, B. M.;
Chisholm, J. D.; Wrobleski, S. T.; Jung, M. J. Am. Chem. Soc. 2002, 124,
12420-12421. Structural revision and synthesis of amphidinolide A: (d)
Trost, B. M.; Harrington, P. E. J. Am. Chem. Soc. 2004, 126, 5028-5029.
Amphidinolide J: (e) Williams, D. R.; Kissel, W. S. J. Am. Chem. Soc.
1998, 120, 11198-11199. Amphidinolide K: (f) Williams, D. R.; Meyer,
K. G. J. Am. Chem. Soc. 2001, 123, 765-766. Amphidinolide P: (g)
Williams, D. R.; Myers, B. J.; Mi, L. Org. Lett. 2000, 2, 945-948. (h)
Trost, B. M.; Papillon, J. P. N. J. Am. Chem. Soc. 2004, 126, 13618-
13619. Amphidinolide R: (i) Kissel, W. S. The Asymmetric Total Syntheses
of Amphidinolides J and R. Ph.D. Thesis, Indiana University, 1998.
Amphidinolide T1: (j) Ghosh, A. K.; Liu, C. J. Am. Chem. Soc. 2003,
125, 2374-2375. Amphidinolides T1, T3, T4, and T5: (k) Fu¨rstner, A.;
A¨ıssa, C.; Riveiros, R.; Ragot, J. Angew. Chem., Int. Ed. 2002, 41, 4763-
4766. (l) A¨ıssa, C.; Riveiros, R.; Ragot, J.; Fu¨rstner, A. J. Am. Chem. Soc.
2003, 125, 15512-15520. Amphidinolide W: (m) Ghosh, A. K.; Gong,
G. J. Am. Chem. Soc. 2004, 126, 3704-3705. Amphidinolide X: (n)
Lepage, O.; Kattnig, E.; Fu¨rstner, A. J. Am. Chem. Soc. 2004, 126, 15970-
15971.
Our interest in the amphidinolide T natural products stemmed
from the presence of the R-hydroxy ketone and homoallylic ester
moieties, both of which are patterns of functional groups that
we have prepared using nickel-catalyzed, alkyne-electrophile
reductive coupling reactions developed in our laboratory.4-6 Our
synthetic strategy represents a novel approach to the T natural
products, based on an alternate ring-closing method (Scheme
(3) For the isolation, structure determination, and biological studies of
Amphidinolides T1-5, see: (a) Tsuda, M.; Endo, T.; Kobayashi, J. J. Org.
Chem. 2000, 65, 1349-1352. (b) Kobayashi, J.; Kubota, T.; Endo, T.;
Tsuda, M. J. Org. Chem. 2001, 66, 134-142. (c) Kubota, T.; Endo, T.;
Tsuda, M.; Shiro, M.; Kobayashi, J. Tetrahedron 2001, 57, 6175-6179.
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A R T I C L E S
Colby et al.
Figure 1. Amphidinolide T family of natural products.
Scheme 1. Macrocyclization Bond Disconnections for Reported
Syntheses of 1
Our plan for installing the hydroxy ketone of 1 and the
“reversed” hydroxy ketone of 4 hinged upon analogous nickel-
catalyzed reductive cyclizations of alkynals 8 and 9 to form
the requisite macrocyclic allylic alcohols 6 and 7. As noted
above, this process would not only close the 19-membered ring
but also concurrently install a stereogenic center. Control over
the configuration of this center would thus be critical to the
syntheses.
Although the positions of the alkyne and aldehyde portions
of the corresponding alkynal cyclization substrates 8 and 9 are
inverted relative to one another, earlier synthetic intermediates
nevertheless share many structural and stereochemical features
(Scheme 3). The synthesis of amphidinolide T1 would neces-
sitate alkynyl acid 10 and homoallylic alcohol 11, while
amphidinolide T4 requires alkenyl acid 12 and hydroxyenyne
13.
1). In contrast to all previously reported syntheses of amphi-
dinolide natural products (i.e. T1 or otherwise), this approach
features the installation of a stereogenic center (>10:1 diaste-
reoselectivity) during the macrocyclization event. Herein, we
disclose the implementation of this strategy in a full account of
our synthesis of amphidinolide T17 and a previously unreported
synthesis of T4.
Retrosynthetic Analysis. The foundation of our strategy for
the synthesis of both amphidinolide T frameworks (the hydroxy
ketone array found in 1 and its reversed positioning in 2-5) is
the use of nickel-catalyzed reductive coupling reactions of
alkynes, the aforementioned intramolecular alkyne-aldehyde
coupling reaction, as well as an intermolecular reductive
coupling of an alkyne and epoxide. As shown in Scheme 2, the
product of the former, an allylic alcohol, would serve as a latent
R-hydroxy ketone moiety.
Both homoallylic alcohols (11 and 13) were predicted to be
available from intermolecular nickel-catalyzed reductive cou-
pling reactions of alkynes and epoxides.5 Alcohol 11, for
example, would be the product of the reaction between alkyne
14 and (R)-n-propyloxirane (16). While aryl alkynes couple with
epoxides with excellent regioselectivity and good yield, in
preliminary investigations of alkynylsilanes as coupling partners,
the homoallylic alcohol product is not formed under the same
conditions, returning only recovered alkyne and epoxide.8 We
planned to exploit this difference in reactivity of alkynes in a
group-selective coupling of diyne 15 with epoxide 16 to form
a hydroxyenyne, which would be elaborated to 13.
Results and Discussion
(4) (a) Huang, W.-S.; Chan, J.; Jamison, T. F. Org. Lett. 2000, 2, 4221-4223.
(b) Colby, E. A.; Jamison, T. F. J. Org. Chem. 2003, 68, 156-166. (c)
Miller, K. M.; Huang, W.-S.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125,
3442-3443. (d) Chan, J.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125,
11514-11515.
(5) Molinaro, C.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 8076-8077.
(6) Several other nickel-catalyzed carbon-carbon bond-forming reactions of
alkynes have been developed by Montgomery: (a) Montgomery, J. Angew.
Chem., Int. Ed. 2004, 43, 3890-3908. (b) Mahandru, G. M.; Liu, G.;
Montgomery, J. J. Am. Chem. Soc. 2004, 126, 3698-3699. (c) Lozanov,
M.; Montgomery, J. J. Am. Chem. Soc. 2002, 124, 2106-2107. (d) Tang,
X.-Q.; Montgomery, J. J. Am. Chem. Soc. 1999, 121, 6098-6099. (e)
Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997, 119, 9065-9066.
(7) Colby, E. A.; O’Brien, K. C.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126,
998-999.
Synthesis of Amphidinolide T1: Construction of C13-
C21 Fragment via Intermolecular Alkyne-Epoxide Reduc-
tive Coupling. We commenced our studies by targeting R,ω-
alkynal 8 in order to investigate catalytic, stereoselective,
reductive macrocyclization en route to amphidinolide T1 (1).
Chiral alkyne 14 was synthesized in a three-step sequence
(Scheme 4), beginning with alkylation of an Evans oxazolidi-
(8) Molinaro, C.; Jamison, T. F. Unpublished results.
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Total Syntheses of Amphidinolides T1 and T4
A R T I C L E S
Scheme 2. Intramolecular Nickel-Catalyzed R,ω-Alkynal Reductive Coupling Strategies
Scheme 3. Intermolecular Alkyne-Epoxide Coupling Strategies
Scheme 4
catalyzed union of these fragments proceeded smoothly, deliver-
ing homoallylic alcohol 11 in very good yield in >98:2 dr and
with >98:2 regioselectivity with respect to both addition across
the alkyne and opening of the epoxide. Optimal conditions were
found when excess epoxide was employed (700 mol % relative
to the alkyne) and the reaction was conducted without additional
solvent. This transformation constitutes an efficient fragment
coupling reaction providing rapid access to the C13-C21
portion of amphidinolide T1 in just four steps.
Synthesis of Amphidinolide T1: Assembly of C1-C12
Fragment. We next turned our attention to the synthesis of
alkynyl acid 10. The key issues to address would be the
installation of a highly substituted tetrahydrofuran ring as well
as a remote carboxylic acid moiety with a stereogenic center at
the R-position. We predicted that the first of these problems
could be solved by a Lewis acid-mediated addition of a
propargyl equivalent to a five-membered cyclic oxocarbenium
ion. This type of reaction has been well-studied by Reissig, who
none with 3-bromo-1-phenyl-1-propyne.9 Cleavage of the
auxiliary with lithium aluminum hydride followed by TBS
protection furnished 14 in 70% yield and 98% ee. The requisite
enantiomerically enriched epoxide 16 was easily prepared by
way of Jacobsen’s hydrolytic kinetic resolution (HKR).10 Nickel-
(10) (a) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science
1997, 277, 936-938. (b) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.;
Tokunaga, M.; Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E.
N. J. Am. Chem. Soc. 2002, 124, 1307-1315.
(9) (a) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737-1739. (b) Savignac, M.; Durand, J.-O.; Geneˆt, J.-P. Tetrahe-
dron: Asymmetry 1994, 5, 717-722.
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A R T I C L E S
Colby et al.
Scheme 5. Woerpel’s Study of Nucleophilic Addition to
Scheme 7. Allenylsilane Addition to Lactol 21a
Oxocarbenium Ions (adapted from ref 12)
demonstrated that substituted five-membered lactols undergo
smooth addition reactions with a variety of nucleophiles when
treated with a Lewis acid, presumably through an oxocarbenium
ion intermediate.11 Woerpel and co-workers have also conducted
extensive studies regarding the stereochemical course of similar
transformations (Scheme 5) in which 2-acetoxy-4,5-cis-disub-
stituted tetrahydrofuran derivatives undergo allylation with a
high degree of stereocontrol to deliver products possessing a
2,4,5-trans-cis relationship across the tetrahydrofuran ring.12
Encouraged by this stereochemical precedent, we needed to
choose an appropriate propargyl nucleophile equivalent13 to
effect the desired addition reaction. At the onset of our
investigations, we focused on Danheiser’s reports14 of allenyl-
silanes as effective propargyl nucleophiles in related Lewis acid-
mediated additions to acyclic acetals, aldehydes, and ketones.
Synthesis of the target oxocarbenium ion precursors began
with an enantioselective addition of a chiral (Z)-crotyl borane
developed by Brown15 to aldehyde 19,16 ultimately setting the
C7-C8 syn relationship (Scheme 6). Hydroboration-oxidation
of the crotylation product furnished a diol which was oxidatively
cyclized, delivering lactone 20 in good yield over the three-
step sequence.17 Reduction of the lactone furnished lactol 21a,
while direct acetate protection of this reduction product provided
acetoxy acetal 21b.
Gratifyingly, we found that the desired propargyl addition was
indeed effected with concomitant removal of the TBS protective
group (Scheme 7) when lactol 21a was treated with boron
trifluoride diethyl etherate and allenylsilane 22, providing the
desired alcohol 23 in 41% yield and in very high diastereose-
lectivity (>95:5).
Several parameters were investigated in an endeavor to
improve the yield of the reaction, including concentration,
temperature, different Lewis acids, addition rate of Lewis acid,
and the use of acetal 21b, but no such efforts were fruitful in
this regard (see Supporting Information for details). Accordingly,
we concentrated on the nucleophilic component, aiming to
increase the nucleophilicity19 of the allene toward the oxocar-
benium ion by using allenylstannane 2420 in place of allenyl-
silane 22. To our satisfaction, the addition proceeded very
smoothly with concomitant complete protiodesilylation, deliver-
ing terminal alkyne 25 in excellent yield (Scheme 8). Subsequent
Sonogashira coupling with iodobenzene furnished target alcohol
23 in near quantitative yield, constituting a vast improvement
over the one-step propargylation with allenylsilane 22 that we
had reported previously.7
Scheme 8. Allenylstannane Addition to Lactol 21a
Scheme 6
With the installation of the substituted tetrahydrofuran ring
achieved by the allenylstannane addition, introduction of the
remaining stereogenic center of carboxylic acid 10 was the next
challenge to address. This was accomplished using an auxiliary-
controlled, diastereoselective alkylation reaction. The pseu-
doephedrine-based method developed by Myers displays very
high diastereoselectivity, allows for use of the iodide as the
limiting reagent, and is well-suited for the alkylation of
unactivated primary alkyl electrophiles.21 Alcohol 23 was
With lactol 21a, acetal 21b, and allenylsilane 2218 in hand,
an investigation of propargylation conditions was conducted.
(11) Schmitt, A.; Reissig, H.-U. Synlett 1990, 40-42.
(12) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K. A. J. Am. Chem.
Soc. 1999, 121, 12208-12209.
(13) Lewis acid-mediated addition of propargyl nucleophiles to 2-acetoxy
tetrahydrofurans is precedented. For the use of propargylmagnesium
bromide, see: (a) Franck, X.; Hocquemiller, R.; Figade`re, B. Chem.
Commun. 2002, 160-161. For the use of a propargyl aluminum species,
see: (b) Dankwardt, S. M.; Dankwardt, J. W.; Schlessinger, R. H.
Tetrahedron Lett. 1998, 39, 4975-4978.
(19) Allylstannanes are reported to be much more nucleophilic compared to
corresponding allylsilanes: (a) Denmark, S. E.; Weber, E. J. J. Am. Chem.
Soc. 1984, 106, 7970-7971. (b) Yamamoto, Y.; Nishii, S.; Yamada, J. J.
Am. Chem. Soc. 1986, 108, 7116-7117. (c) Sato, T.; Otera, J.; Nozaki, H.
J. Org. Chem. 1990, 55, 6116-6121. Allenylstannanes have also been
shown to add to thioacetals under Lewis acidic conditions: (d) Sato, T.;
Okura, S.; Otera, J.; Nozaki, H. Tetrahedron Lett. 1987, 28, 6299-6302.
(e) Takeda, T.; Ohshima, H.; Inoue, M.; Togo, A.; Fujiwara, T. Chem.
Lett. 1987, 1345-1348.
(14) Danheiser, R. L.; Carini, D. J. J. Org. Chem. 1980, 45, 3925-3927.
(15) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919-5923.
(16) Marshall, J. A.; Shearer, B. G.; Crooks, S. L. J. Org. Chem. 1987, 52,
1236-1245.
(20) Reported to propargylate enones in a 1,4 addition mode under Lewis acidic
conditions: Haruta, J.; Nishi, K.; Matsuda, S.; Akai, S.; Tamura, Y.; Kita,
Y. J. Org. Chem. 1990, 55, 4853-4859.
(17) This sequence of functional group manipulations was performed as reported
in ref 12.
(18) Prepared according to: Westmijze, H.; Vermeer, P. Synthesis 1979, 390-
(21) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.;
Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496-6511.
392.
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Total Syntheses of Amphidinolides T1 and T4
A R T I C L E S
Scheme 9. Synthesis of Alkynyl Acid 10
the best conditions proved to be a 20 mol % Ni(cod)2/40 mol
% tributylphosphine combination, giving 6 in a 44% yield, again
in >10:1 dr.24
Two features of the macrocyclization are noteworthy. First,
we observed that the sense of induction matches the Felkin-
Anh model25 of nucleophilic addition to chiral aldehydes, and
we therefore hypothesized that the configuration at C14 of the
alkynal is largely responsible for the sense of stereoinduction
in the intramolecular coupling (macrocyclization). Moreover,
the complete diastereocontrol observed in the reductive mac-
rocyclization was quite surprising as intermolecular couplings
of aldehyde 29 and alkyne 30 were virtually nonselective
(Scheme 12), affording allylic alcohol 31 in 1.5:1 dr. Second,
the intramolecular alkyne-aldehyde reductive coupling reaction
used in Scheme 11 shortens the overall synthesis by several
steps relative to an intermolecular coupling strategy that would
require protection of both alkynyl acid 10 and alcohol 11 (and
subsequent deprotection (prior to macrolactonization)).
Synthesis of Amphidinolide T1: Endgame. Macrocycliza-
tion of alkynal 8 overcame a significant hurdle in the synthesis
of 1; all of the stereogenic centers of 1 had been set, and all of
the carbon atoms within the ring framework of 1 were present
in 6. The remaining challenge was differentiation of the two
benzylidene groups at C12 and C16. Specifically, oxidative
cleavage of the C12 benzylidene to a ketone and conversion of
the C16 benzylidene to an exo-methylidene group were required.
We decided to exploit the difference in steric congestion
around the carbon atoms at issue and accordingly protected the
allylic hydroxyl group at C13 with a TBS group (Scheme 13).
Subsequent global ozonolysis produced diketone 32 possessing
very different environments around the two carbonyl groups.
We predicted that the resultant C16 carbonyl (flanked by two
CH2 groups) would be more susceptible to nucleophilic attack
than the C12 carbonyl (flanked by a bulky silyl ether and a
tetrahydrofuran â to C12), and treatment with a methylenating
reagent would lead to the functional group pattern present in 1.
As we set our sights upon selective methylenation, we took
into account that both carbonyl groups possessed â-oxygen
substituents that might act as leaving groups under strongly basic
conditions. We first investigated the Oshima reagent (Zn, CH2-
Br2, TiCl4),26 as well as the Lombardo-modified reagent “low-
temperature aged”,27 but in both cases only diketone was
recovered. Standard Takai conditions (Zn, CH2I2, TiCl4)28 were
also unsuccessful, but replacement of TiCl4 by ZrCl4 and the
addition of lead(II) chloride29 resulted in clean methylenation
at the C16 carbonyl furnishing the desired monoketone in 65-
75% yield.30
converted to alkyl iodide 26, which was an effective electrophile
for the desired alkylation reaction, proceeding in near-quantita-
tive yield and in excellent diastereoselectivity (Scheme 9). The
alkylated amide underwent base-promoted hydrolysis to furnish
alkynyl acid 10 in excellent yield and in >95:5 dr.
Synthesis of Amphidinolide T1: Fragment Coupling and
Reductive Macrocyclization. Enantiomerically pure homoal-
lylic alcohol 11 and enantiomerically pure alkynyl acid 10 were
joined in a DCC-mediated ester formation, affording 27 in 72%
yield (Scheme 10). While this C-O bond formation was
certainly satisfactory, we investigated an alternative, stereose-
lective fragment coupling via alkylation of an enolate derived
from the propionate ester of alcohol 11. This approach would
indeed save one step relative to the route described above, but
it would nevertheless have to surpass the very high efficiency
and complete stereocontrol provided by the Myers’ asymmetric
alkylation method. Treatment of ester 28 with LDA and iodide
26 did indeed afford 27 (converging with the original route),
but this process was nearly nonselective (1.6:1 dr, favoring the
undesired diastereomer). Clearly, therefore, this strategy modi-
fication did not result in any improvement in the preparation
of ester 27.
After two functional group manipulations (TBS removal with
TBAF and oxidation with the Dess-Martin periodinane re-
agent), we were poised to investigate conditions to form the
19-membered ring via an intramolecular alkyne-aldehyde
reductive coupling reaction (Scheme 11). We began our studies
with an achiral catalyst consisting of Ni(cod)2 and tributylphos-
phine, which had been very successful in other alkyne-aldehyde
intramolecular reductive coupling reactions in our group.22
A
dilute solution of alkynal 8 (0.05 M in toluene), 10 mol % nickel,
20 mol % phosphine, and triethylborane was stirred at ambient
temperature, but no reaction was observed (only 8 was isolated).
A screening of phosphine ligands was conducted, but the desired
cyclization was not observed in any case. We next explored
the variables of concentration and temperature and were pleased
to find that tributylphosphine/Ni(cod)2 promoted cyclization
when the reaction mixture was heated to 60 °C, albeit in low
yield (25-30%). Nevertheless, the stereoselectivity of the
cyclization was outstanding; macrocyclic allylic alcohol 6 was
isolated in greater than 10:1 diastereoselectivity possessing the
(S)-carbinol configuration, corresponding to that found in the
natural product amphidinolide T1 (1).23 Further optimization
efforts revealed that a higher catalyst loading improved the yield;
Finally, treatment of this product with HF-pyridine promoted
clean conversion (>90% yield) to amphidinolide T1 (Scheme
(25) (a) Che´rest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 18, 2199-
2204. (b) Che´rest, M.; Felkin, H. Tetrahedron Lett. 1968, 18, 2204-2208.
(c) Anh, N. T.; Eisenstein, O. NouV. J. Chim. 1977, 1, 61-70. (d) Anh, N.
T. Top. Curr. Chem. 1980, 88, 145-162.
(26) Takai, K.; Hotta, Y.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1978, 19,
2417-2420.
(27) Lombardo, L. Org. Synth. 1987, 65, 81.
(28) Hibino, J.; Okazoe, T.; Takai, K.; Nozaki, H. Tetrahedron Lett. 1985, 26,
5579-5580.
(29) Lead effects: (a) Takai, K.; Kakiuchi, T.; Kataoka, Y.; Utimoto, K. J. Org.
Chem. 1994, 59, 2668-2670. Zirconium alkylidene reagents: (b) Hartner,
F. W., Jr.; Schwartz, J.; Clift, S. M. J. Am. Chem. Soc. 1983, 105, 640-
641. (c) Tucker, C. E.; Knochel, P. J. Am. Chem. Soc. 1991, 113, 9888-
9890.
(22) Chan, J.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 10682-10691.
(23) Determined by Mosher ester analysis and ultimate conversion to 1.
(24) Remaining material appeared to be a number of decomposition products
of the alkynal that could not be identified.
(30) Work in our laboratory has shown that this system is effective for the
methylenation of sterically hindered ketones. Jeso, V.; Jamison, T. F.
Unpublished results.
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Colby et al.
Scheme 10. Contrasting Fragment Coupling Strategies
Scheme 11. Nickel-Catalyzed Reductive Macrocyclization
Scheme 13. Synthesis of 1 via Selective Methylenation
Scheme 12. Intermolecular Reductive Coupling Strategy
Scheme 14. Site-Selective Diyne-Epoxide Reductive Coupling
13), whose spectroscopic, spectrometric, and physical properties
matched those reported for natural product 1.
Synthesis of Amphidinolide T4 Framework. Completion
of the total synthesis of 1 indicated that our strategy of reductive
macrocyclization was indeed a viable route to amphidinolide
T1. Nevertheless, a critical issue in using this strategy for the
synthesis of other members (T2-5) was the reversed hydroxy
ketone pattern at C12 and C13 (see Figure 1). In our next
synthetic undertaking, we set out to address this issue by
studying the reductive cyclization of alkynal 9, and whether it
would exert a high degree of substrate diastereocontrol in a
cyclization using an achiral catalyst system since it contains
â-branching with respect to the aldehyde instead of R-branching
(Scheme 4).
Synthesis of Amphidinolide T4 Framework: Construction
of C13-C21 Fragment via Site-Selective, Intermolecular
Diyne-Epoxide Reductive Coupling. Synthesis of the requisite
alkynal 9 began with an investigation of the viability of a site-
selective alkyne-epoxide reductive coupling of diyne 15.
Alcohol 33 (previously synthesized in the T1 synthesis, Scheme
4) was oxidized to the aldehyde, converted to the dibromoolefin,
and finally exposed to methyllithium and chlorotrimethylsilane
to arrive at diyne 15 (Scheme 14). We found that 15 did indeed
undergo coupling with (R)-propyloxirane to give the desired
hydroxyenyne 34 with >95:5 regioselectivity and >95:5 dias-
tereoselectivity. While the crude product mixture was contami-
nated with products of polymerization of the alkyne, there was
no evidence of epoxide coupling at the alkynylsilane. Coupling
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Total Syntheses of Amphidinolides T1 and T4
A R T I C L E S
Scheme 15. Synthesis of Alkenyl Acid 12
Scheme 16. Routes to Alkynals 9a,b
Synthesis of Amphidinolide T4 Framework: Reductive
Macrocyclization and Elaboration to T4. Both 9a and 9b were
subjected to the nickel-catalyzed reductive coupling conditions
found to promote macrocyclization in our earlier synthesis of
1. Upon addition to a warm solution of Ni(cod)2, tributylphos-
phine, and triethylborane, 9a and 9b underwent reductive
cyclization to afford the desired macrocyclic allylic alcohols
(Scheme 17). In both cases, the diastereoselectivity was very
high (>10:1 dr). TBS protection and ozonolysis of the two
alcohols led to diketone 36, which was selectively methylenated
product 34 was converted to the target homoallylic alcohol 13
by treatment with TBAF and subsequent Sonogashira coupling
with iodobenzene. The site-selective epoxide coupling stream-
lined the synthesis of the C13-C21 fragment by directly
introducing the necessary alkyne at C13 rather than starting from
T1 coupling product 11 and elaborating to the alkyne. The
former route saves several steps, thus compensating for the
moderate yield of the diyne coupling reaction.
1
and deprotected with HF-pyridine. The H NMR data of the
final product matched that of amphidinolide T4 (4) and differed
significantly from its C12 diastereomer T3 (3), revealing the
stereochemical outcome of the reductive cyclization. A com-
1
Synthesis of Amphidinolide T4 Framework: Construction
of C1-C12 Alkenyl Acid, Fragment Coupling, and Alkynal
Synthesis. Alkenyl acid 12 was targeted next to advance the
investigation of the T3/T4 synthesis. This acid was synthesized
in a route similar to alkynyl acid 10 (Scheme 15). Lewis acid-
mediated allylation of lactol 21a by allyltrimethylsilane pro-
ceeded in excellent yield to deliver the primary alcohol, which
underwent smooth iodination to afford iodide 35. The iodide
was incorporated into an asymmetric Myers’ alkylation-
hydrolysis sequence similar to that used in the T1 synthesis
affording acid 12 in 88% yield over two steps and in
>95:5 dr.
parison of the diagnostic region of the H NMR spectra of
natural 3, natural 4, and synthetic 4 is shown in Figure 2.
Scheme 17. Reductive Macrocyclizations of 9a,b and Synthesis
of 4
Fragment coupling was carried out by way of a DCC-
mediated esterification which proceeded in 72% yield (Scheme
16). As we sought to study ring-closing reductive cyclizations,
we examined methods of selective, oxidative cleavage of the
terminal alkene that would afford alkynal 9a. This target
compound (with the benzylidene group at C16 intact) was the
logical starting point for the “reversed” reductive coupling
strategy as the T1 alkynal also possessed a benzylidene at this
position and underwent cyclization successfully. We found that
9a could indeed be prepared by a dihydroxylation-periodate
cleavage sequence (A, Scheme 16), but overoxidation produced
9b, and, moreover, the overall mass recovery of the process
was low (<20% yield on 10 mg scale, 3:2 ratio of 9a to 9b).
Given these difficulties, we reconsidered our tactics and realized
that a ketone might possibly be tolerated at C16 as ketones are
much less reactive than aldehydes under our nickel-catalyzed
reductive coupling conditions and, in most cases, inert.31 This
alternative oxidation was accomplished via ozonolysis (B,
Scheme 16), which cleaved both alkenes while leaving the
alkyne intact to deliver 9b in very good yield.32
Synthesis of Amphidinolide T4 Framework: Comparison
of Inter- and Intramolecular Reductive Coupling Strategies.
As we had done in the T1 series (Scheme 12), we sought to
compare the corresponding intermolecular alkyne-aldehyde
reductive coupling for the 3-4 framework. Interestingly, nickel-
catalyzed coupling of ketoalkyne 37 and tetrahydrofuranyl
aldehyde 38 resulted in a mixture of products that have been
tentatively assigned as various elimination products and the
intramolecular hemiketal of the desired allylic alcohol. In an
attempt to identify reaction products with certainty, the coupling
was repeated with immediate silyl protection of the crude
product mixture. As shown in Scheme 18, the isolated product
was dihydropyran 39 as a 2:1 mixture of diastereomers,
confirming our hypothesis that the coupling product was
undergoing hemiketal formation and dehydration upon treatment
with TBSCl. Not only did this result once again point to a strong
conformational bias in the cyclization process that does not exist
(32) Ozonolysis was followed by exposure to dimethyl sulfide affording 9b and
another product, determined to be the ozonide at terminal position.
Treatment of the ozonide with triphenylphosphine promoted clean conver-
sion to 9b, giving an 80% combined yield of 9b. Direct reductive workup
with triphenylphosphine resulted in much lower yields. See Supporting
Information for more detail.
(31) Many alkyne-aldehyde couplings may be conducted in acetone without a
decrease in yield. Nevertheless, a notable exception exists, that being an
intramolecular, Ni-catalyzed alkyne-ketone coupling observed during
studies directed toward the synthesis of terpestacin, ref 22.
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A R T I C L E S
Colby et al.
1
Figure 2. Diagnostic region of the H NMR spectra of 3 and 4.
Scheme 18. Intermolecular Coupling Study
Scheme 19. Reductive Cyclizations of 9b with P-Chiral Ferrocenyl
Ligands
in the intermolecular process but also that the macrocycle
prevents formation of undesired byproducts such as dihydro-
pyrans related to 39.
Investigation of Substrate Control in Reductive Macro-
cyclizations and Development of a Stereoselectivity Model.
With the successful nickel-catalyzed macrocyclization of 9b
using an achiral catalyst system, we endeavored to employ a
chiral catalyst to overcome the inherent bias for the (S)-carbinol
configuration of T4 (4), which, if successful, would provide an
entry into the T3 stereochemical pattern. We first examined the
ligand (S)-neomenthyldiphenylphosphine (NMDPP)33 in com-
bination with Ni(cod)2 and triethylborane but were disappointed
to find that the catalyst system was not stable toward heating
and cyclization did not occur. We next turned to P-chiral
ferrocenyl ligands developed in our laboratory.4b We were
pleased to find that 9b did indeed undergo cyclization when
heated with a catalytic amount of Ni(cod)2 and (S)-ferrocenyl-
methylphenylphosphine and stoichiometric triethylborane, pro-
ducing allylic alcohol 7b in 30% yield and >10:1 dr. Interest-
(33) During intermolecular reductive coupling studies of aldehydes and aryl
alkynes in our laboratory,4c NMDPP emerged as a uniquely powerful
promoter of asymmetric Ni-catalyzed coupling reactions.
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Total Syntheses of Amphidinolides T1 and T4
A R T I C L E S
original hypothesis and as evidenced by entries 1 and 2, the
Felkin-Anh model clearly does not apply in the case of the T1
series. That is, the configuration of the stereogenic center
adjacent to the aldehyde undergoing reductive coupling with
the alkyne has no effect whatsoever on the sense of induction.
A minimum of 8:1 diastereoselectivity favoring the (S) config-
uration was observed in both cases.
The results of the T4 series of macrocyclizations (entries 3-6)
are especially striking since the same sense and degree of
stereoselectivity are observed for two different alkynals (9a
(benzylidine at C16) and 9b (ketone at C16)) and, in the case
of 9b, for three very different ligands (achiral, (R), or (S)). That
the analogous “epi-methyl” (entry 7) experiment did not afford
the desired product unfortunately prevents direct analysis of the
effect of this stereogenic center upon the sense and degree of
induction in the reductive macrocyclizations.
Figure 3. epi-C14 alkynals.
Scheme 20. Inverted C14 Methyl Effect on Reductive
Macrocyclizations
While we hesitate to infer too much information from a direct
comparison of the T1 and T4 series of macrocyclizations, in
which the positions of the alkyne and aldehyde have been
reversed, we nevertheless propose a simple model of stereoin-
duction that is applicable to both of these cases (Figure 4). The
elements of the analysis that led to this rationale are as follows:
1. We have invoked an oxanickellacyclopentene4c,6e,22,35 as
an approximation of the transition state of the reductive coupling.
2. The primary consideration in our conformational analysis
was strain (torsional and steric) developing in the vicinity of
the site of reactivity.36
ingly, when the opposite enantiomer of the ligand was utilized,
7b was also afforded in >10:1 dr (and 25% yield) with the
same configuration at C12 (T4 configuration, Scheme 19).
3. Both possible product diastereomers were subjected to the
same analysis, and a rough comparison was made between the
two.
This result demonstrated that these stereoselective macrocy-
clizations are under complete substrate control and are consistent
with our growing hypothesis that both alkynals 8 and 9b are
highly conformationally constrained during the reductive mac-
rocyclization process. As noted above, we initially suspected
that the configuration of the C14 methyl group in both cases
(adjacent to the aldehyde group in 8 and adjacent to the alkyne
in 9) played a significant role in inducing this bias.
Figure 4a represents our proposed model that minimizes the
unfavorable interactions in the transition state of the catalytic
macrocyclization used to prepare amphidinolide T1. For clarity,
three key 1,3-interactions are highlighted although many more
are incorporated into the proposed model. The conformation
shown possesses the fewest number of gauche+-gauche- (“syn-
pentane”),37 A1,3 strain,38 and related 1,3-interactions for this
diastereomer. For example, orienting the bonds highlighted in
red in the same direction and doing the same for the blue pair
and the three black (bold) bonds generates no syn-pentane-like
interactions in any of these three cases. (Not emphasized in this
drawing is the fact that several other 1,3-interactions are also
avoided.) On the contrary, all other possible conformations
induce at least one syn-pentane-like interaction.
The net effect of this arrangement is that the carbon-carbon
bonds connected by the loop representing the rest of the
macrocycle are pointed in the same direction (see asterisked
bonds). The remaining 12 atoms in the macrocycle are thus
easily accommodated without inducing severe steric and/or
torsional interactions.
To probe this hypothesis, i.e., the relevance of the Felkin-
Anh model of stereoselectivity to these macrocyclizations, we
synthesized alkynals 40 and 41 with the opposite configuration
at C14 (Figure 3). Syntheses of both epi-C14 alkynals com-
menced with ent-33 (prepared using the R enantiomer of the
Evans auxiliary) and followed the respective T1 and T4
syntheses exactly. The inverted methyl configuration did not
affect either of the alkyne-epoxide or selective diyne-epoxide
reductive coupling reactions and subsequent elaboration afforded
the alkynals (details included in the Supporting Information).
With the alkynals in hand, we were poised to examine
reductive macrocyclization conditions. We found that alkynal
40 underwent cyclization when heated in the presence of 20
mol % Ni(cod)2, 40 mol % tributylphosphine, and excess
triethylborane in 35% yield with high diastereoselectivity (8:1
dr). Analysis of macrocyclic alcohol 42 using the Mosher
method34 revealed that the major diastereomer possessed the S
configuration at the carbinol center (Scheme 20). Interestingly,
under the same conditions, alkynal 41 did not undergo cycliza-
tion (the only recovered compound was unreacted 41).
When the same analysis was applied to the diastereomer not
observed in this cyclization, the structure in Figure 4b was
generated. As can be seen, the bonds that are connected by the
(34) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512-519.
(35) Miller, K. M.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 15342-15343.
(36) This approach is likely an oversimplification, as it ignores the effects of
other stereogenic centers, e.g. those in the tether linking the alkyne and
the aldehyde. Related experiments with other sets of diastereomers would
directly test these influences and possibly result in further refinement (or
revision) of the model proposed herein.
The results of this set of coupling reactions (summarized in
Table 1) required significant revision of our model of stereoin-
duction in the catalytic macrocyclizations. Contrary to our
(37) Hoffman, R. W. Chem. ReV. 1989, 89, 1841-1860.
(38) Wiberg, K. B.; Murcko, M. A. J. Am. Chem. Soc. 1988, 110, 8029-8038.
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A R T I C L E S
Colby et al.
Table 1. Macrocyclization Experiments
Figure 4. Conformational analysis of possible diastereomers in catalytic, stereoselective macrocyclizations leading to amphidinolides T1 (1) and T4 (4).
loop are now pointed in different directions, approximately 120°
relative to one another. Moreover, the loop in this case represents
only 9 additional atoms, and model building suggests that
requiring this shorter chain to span the required distance is not
nearly as straightforward as was the case in the other diaste-
reomer (Figure 4a).
A particularly satisfying feature of this model is that it can
in fact be used to explain the observed stereochemical outcomes
of the macrocyclizations that were used in the synthesis of
amphidinolide T4. In other words, despite the fact that the “ends
are reversed” so to speak, minimization of a very similar set of
developing steric interactions accounts for the sense of induction
in both the T1 and T4 series. As shown in Figure 4c,d, the net
effect of this analysis for the T4 series is also strikingly similar
to that in the T1 series. In Figure 4a (T1) and 4c (T4), 12 atoms
are available to join the two ends (which are pointed in the
same direction), whereas Figure 4b,d suggests that a much
greater demand would be required of the 9 atoms in the chain.
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Total Syntheses of Amphidinolides T1 and T4
A R T I C L E S
Figure 5. Conformational analysis of the products of macrocyclization of an alkynal diasteromeric (at C14) to that used in synthesis of 1.
Figure 6. Unified model of stereoinduction for catalytic macrocyclizations.
A comparison of the results of the T1 series of macrocy-
clizations and of the 14-epi-T1 series is also worthy of comment
(Figures 4a,b, 5, and 6). The goal of these exercises was to
account for the initially counterintuitive observation that the
stereogenic center adjacent to the site of the aldehyde had no
effect on the sense of induction, i.e., that the Felkin-Anh model
did not apply in this case. One must be careful, however, in
drawing too much from this comparison, especially since the
diastereoselectivity in the 14-epi-T1 series was not “complete”,
as it was in the T1 and T4 series. To a first approximation, 8:1
dr at 60 °C represents a difference in energy of the two transition
states of about 1.4 kcal‚mol-1, a rather small value when
compared to all the possible interactions in these complex
systems.
Nevertheless, as shown in Figure 5, low-energy conformations
for the diastereomers observed in the macrocyclizations in the
“epi-methyl-T1” series were generated using the criteria in the
other cases, and they are reminiscent of those for the corre-
sponding diastereomers in the T1 series (Figure 4a,b). The
essence of this comparison is summarized in Figure 6.
To summarize, our conclusion from these analyses is that
the strongest effect upon the sense of induction is minimization
of 1,3-interactions near the site of reactivity in the transition
state. Moreover, branching (i.e. two substituents that are not
hydrogen) at the carbon adjacent to the aldehyde (C14 in these
cases) can be accommodated without energetic penalty since
C12 is sp2 hybridized. That is, because of the absence of a
substituent at C12, there are no 1,3-interactions with the
substituents at C14, and thus the effect on stereoselectivity of
branching adjacent to the aldehyde is dramatically attenuated.
In other words, as long as the remainder of the nascent
macrocycle can be accommodated without inducing severe
unfavorable interactions, the configuration adjacent to the
reacting aldehyde is of no consequence in determining the
stereochemical outcome. Rather, it is the minimization of other
interactions around the site of reaction that has the greatest
effect. This hypothesis is not new in its own right of course,39
but it does suggest a unifying strategy that might be exploited
in related stereoselective macrocyclizations.
Conclusion. In summary, we have found that intramolecular
alkyne-aldehyde couplings are efficient methods for closing
the 19-membered ring present in the amphidinolide T frame-
work. The simultaneous installation of the carbinol stereogenic
center found in 1 and 4 occurred with complete diastereocontrol.
This reductive macrocyclization approach proved to be far
superior to the corresponding intermolecular reductive coupling
strategy, not only with respect to stereoselectivity but also in
the overall number of synthetic steps necessary to access the
natural products.
Acknowledgment. We are grateful to Anna K. Hirsch
(Cambridge University-MIT Exchange Program) for experi-
mental assistance, and Dr. Li Li for obtaining mass spectrometric
data for all compounds. E.A.C. thanks the American Society
for Engineering Education (NDSEG Fellowship) and K.C.O.
thanks the Thomas A. Spencer Endowed UROP Fund (MIT).
We also thank the National Institute of General Medical
Sciences (GM-063755), NSF (CAREER CHE-0134704), Am-
gen, Boehringer Ingelheim, GlaxoSmithKline, Johnson &
Johnson, Merck Research Laboratories, and Pfizer for generous
financial support. The NSF (CHE-9809061 and DBI-9729592)
and NIH (1S10RR13886-01) provide partial support for the MIT
Department of Chemistry Instrumentation Facility.
Supporting Information Available: Experimental procedures
and data and 1H NMR spectra for 1, 4, 6-15, 20-21, 23, 25-
28, 32-36, 40-42, and naturally occurring 1 and 4 (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
(39) For an in-depth study of situations in which developing 1,3-interactions
(syn-pentane-like) better account for the observed sense of stereoinduction
in additions to chiral aldehydes than the Felkin-Anh model; see: Roush,
W. R. J. Org. Chem. 1991, 56, 4151-4157.
JA042733F
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