The Transannular Diels-Alder Reaction - ACS Organic Division

The Transannular Diels-Alder
Reaction: Applications in
Complex Molecule Synthesis
Craig R. Smith
Department of Chemistry, The Ohio State University, 100 W. 18 th Avenue, Columbus,
Ohio 43210
csmith@chemistry.ohio-state.edu
Me
RO
ABSTRACT
The Diels-Alder (DA) reaction is arguably one of the most powerful carbon-carbon bond forming reactions in
synthesis due to atom economy, broad versatility, and high levels of stereocontrol. When the broad features of
Diels-Alder chemistry are implemented in transannular systems, the results have been especially impressive. The
transannular Diels-Alder (TADA) reaction will be discussed in the context of four recently disclosed syntheses.
The discovery of the Diels-Alder reaction in 1928, 1 or
rather the proper identification of the cycloaddition
adduct of cyclopentadiene and quinone, marked a
tremendous advance in the field of organic synthesis.
The visionary insight of Diels and Alder predicted the
importance of the reaction in natural product synthesis,
and in particular, to the synthesis of terpenes,
sesquiterpenes and alkaloids. The first application of this
pericyclic reaction in natural product synthesis occurred
more than twenty years after its discovery. In 1951,
Stork et al. applied the Diels-Alder reaction to the
stereocontrolled synthesis of cantharidin, 2 while only a
few months later, the pericyclic process was employeed
in the first total synthesis of morphine. 3 Other landmark
applications of the intermolecular Diels-Alder reaction
e
(1) Diels, O.; Alder, K. Justus Liebigs Ann. Chem. 1928, 460, 98.
(2) (a) Stork, G.; Van Tamalen, E. E.; Friedman, L. J.; Burgstahler,
A. W. J. Am. Chem. Soc. 1951, 73, 4501. (b) Stork, G.; Van Tamalen,
E. E.; Friedman, L. J.; Burgstahler, A. W. J. Am. Chem. Soc. 1953, 75,
384.
(3) (a) Gates, M.; Tschudi, G. J. Am. Chem. Soc. 1952, 74, 1109. (b)
Gates, M.; Tschudi, G. J. Am. Chem. Soc. 1956, 78, 1380. (c) Gates, M.
J. Am. Chem. Soc. 1950, 72, 228.
Me
O
O t OR
Me
OR'
Me
Bu
O
RO
R=TES,R'=TMS
are the syntheses of cortisone and cholesterol 4 disclosed
by Woodward et al. in 1952, and to forge the D,E bicycle
of reserpine 5 (4) in 1956 (Scheme 1).
Scheme 1. DA in Woodward’s Synthesis of 4.
O
endo TS
O
O
H
PhH
DA
+
heat O
D E
O
1
CO2Me
2
MeO2C
H
O CO2Me
3
MeO
Me
t BuO
OR
Me H
Tandem Transannular Diels-Alder Sequence
H
O
R'O
O
Me
Me
H
A
B
N
H H
C
N
D H
H E
O
MeO2C O
Reserpine (4)
OMe
OMe
OMe
OMe
steps

As intermolecular variations of the DA have been
employed in a number of syntheses, more recent
endevours have used the intramolecular DA with great
efficiency. Here, the benefit is that the product outcome
can be predicted with high accuracy due to the
stereochemical requirements of the pre-existing
functionalities. The power of the DA was again
demonstrated by Corey et al. in a brilliant synthesis of
gibberellic acid, 6 in which a chemo- and regioselective
intermolecular DA introduced the relative
stereochemistry in the B and C rings of the final product,
followed by an intramolecular substrate-controlled DA to
forge the A ring of gibberellic acid.
Deslongchamps envisioned that a TADA would
possess high chemo-, regio-, and diastereoselectivity. It
would also generate highly complex carbocyclic systems
as a result of both entropic activation and conformational
restraints in the macrocyclic environment. His seminal
work in the area layed the foundation for future synthetic
endevours, four of which will be examined in detail.
Deslongchamps influential contributions include TADA
reactions of 13-membered macrocyclic trienones, 7 TADA
reactions of 14-membered macrocycles, 8 dienedienophile
reactivity studies for the TADA, 9 and the
synthesis of a number of natural products including
cassaine A (5) 10 and aphidicolin (6, Figure 1). 11
Deslonchamps noted, 12 “…the complexity and power of
HO
H
Figure 1. Cassaine A and Aphidicolin.
H
O
O
Cassaine A (5)
O
N
HO
HO
H
Aphidicolin (6)
the TADA strategy arises from a judicious choice of
substituents that will govern the conformation adopted by
the macrocycle at the transition state level, via
transannular steric repulsion and electronic interactions,”
or more plainly, an in-depth analysis of the macrocycle
and the potential transition states leads to a high fidelity
e
(4) Woodward, R. B.; Sondheimer, F.; Taub, D.; Heusler, K.;
McLamore, W. M. J. Am. Chem. Soc. 1952, 74, 4223.
(5) (a) Woodward, R. B.; Bader, F. E.; Bickel, H.; Frey, A. J.;
Kierstead, R. W. J. Am. Chem. Soc. 1956, 78, 2023. (b) Woodward, R.
B.; Bader, F. E.; Bickel, H.; Frey, A. J.; Kierstead, R. W. J. Am. Chem.
Soc. 1956, 78, 2657.
(6) (a) Corey, E. J.; Danheiser, R. L.; Chandrasekaran, S.; Siret, P.;
Keck, G. E.; Gras, J.-L. J. Am. Chem. Soc. 1978, 100, 8031. (b) Corey,
E. J.; Danheiser, R. L.; Chandrasekaran, S.; Keck, G. E.; Gopalan, B.;
Larsen, S. D.; Siret, P.; Gras, J.-L. J. Am. Chem. Soc. 1978, 100, 8034.
(7) (a) Baettig, K.; Dallaire, C.; Pitteloud, R.; Deslongchamps, P.
Tetrahedron Lett. 1987, 28, 5249. (b) Baettig, K.; Marinier, A.;
Pitteloud, R.; Deslongchamps, P. Tetrahedron Lett. 1987, 28, 5253. (c)
Bérubé, G.; Deslongchamps, P. Tetrahedron Lett. 1987, 28, 5255.
(8) (a) Lamothe, S.; Ndibwani, A.; Deslongchamps, P. Tetrahedron
Lett. 1988, 29, 1641. (b) Marinier, A.; Deslongchamps, P. Tetrahedron
Lett. 1988, 29, 6215.
OH
OH
prediction of the stereocontrolled assembly of densely
populated carbocyclic arrays.
Recently, a number of biologically and structurally
interesting carbocyclic natural products have been
assembled via the TADA reaction including (+)-
FR182877, (+)-macquaramicin A, (-)-spinosyn A, and
(+)-superstolide A. Among these compounds, (+)-
FR182877 is interesting as it possesses a highly oxygen
and carbon functionalized hexacyclic core, 12 stereogenic
centers, and significant microtubule stabilizing activity.
In 2001, Sorensen and co-workers 13 suggested that 11
Me
R'O
Scheme 2. Sorensen’s Synthesis of (+)-FR182877.
Bu t O2C
RO
CO 2Me
O
1. PhSeBr
2. mCPBA
Me
OR
OR
Pd2dba3
R=TES
R' = TMS
Bu t O2C
Me
R'O
Me
Me
Me
7 8
Me
Me
RO
O
O t OR
Me
OR'
Me
Bu
O
Me
9 and (Z)-isomer
Me
H
H
OR
H
H CO2Bu
H
O
Me
OR'
t
Me
H
steps
H
Me
H
OH
H
H O
H
O O
H
Me
Me
10 (+)-FR182877 (11)
O
HO
Me
CHCl3
40°C
may arise from a polyunsaturated linear biosynthetic
intermediate that undergoes a cascade of intramolecular
reactions. To date, Sorensen’s synthesis 14 (Scheme 2) of
(+)-FR182877 is the supreme expression of the TADA in
action. The synthesis of the key 19-membered
macrocyclic precursor culminated, after 16 steps, with a
palladium-mediated Tsuji-Trost reaction. Heating the
macrocycle in CHCl3 at 40°C induced the sequential
TADA and hetero-TADA reactions that stereoselectively
e
(9) (a) Cantin, M.; Xu, Y.-C.; Deslongchamps, P. Can. J. Chem.
1990, 68, 2144. (b) Roberge, J. Y.; Giguere, P.; Soucy, P.; Dory, Y. L.;
Deslongchamps, P. Can. J. Chem. 1994, 72, 1820.
(10) Pheonix, S.; Bourque, E.; Deslongchamps, P. Org. Lett. 2000, 2,
4149.
(11) (a) Bélanger, G.; Deslongchamps, P. Org. Lett. 2000, 2, 285. (b)
Bélanger, G.; Deslongchamps, P. J. Org. Chem. 2000, 65, 7070.
(12) Deslongchamps, P. Pure & Appl. Chem. 1992, 64, 1831.
(13) (a) Vanderwal, C. D.; Vosburg, D. A.; Weiler, S.; Sorensen, E. J.
Org. Lett. 1999, 1, 645. (b) Vanderwal, C. D.; Vosburg, D. A.;
Sorensen, E. J. Org. Lett. 2001, 3, 4307.
(14) Vosburg, D. A.; Vanderwal, C. D.; Sorensen, E. J. J. Am. Chem.
Soc. 2002, 124, 4552.
Me
OR
OR
Me

fashioned 10 as a single diastereomer. In a single step,
the overall process generated a pentacyclic structure with
concomitant installation of seven contiguous stereogenic
centers in 40% isolated yield. Most notably, this work
elicited the first example of a tandem or sequential
TADA reaction, which highlights the utility of the TADA
in complex molecule synthesis. As Deslongchamps
eluded to previously, the capacity of the tandem reaction
is governed by entropic and enthalpic activation in the
macrocycle with product geometry determined by
transannular repulsion and electronic interactions in the
transition state of the pericyclic reaction. Shortly after
Sorensen’s disclosure of (+)-FR182877, both Evans 15 and
Sorensen 13 published syntheses of the natural enantiomer,
(-)-FR182877, both utilizing TADA strategies.
The macquarimicins are a polyketide based class of
natural products that are comprised of a cistetrahydroindanone
ring, a β-keto-δ-lactone, and a 10membered
carbocycle. Biologically, these compounds
MeO 2CO
MeO
Scheme 3. Synthesis of (+)-Macquarimicin A.
Me
MPMO
Pd 2dba 3
MeO2C
OR
O O OR OR R=TBS
O
12 13
H
Me
steps
H
H
O
HO
steps
Me OMPM
OR
Me
OMPM
H
O
BHT
toluene
130°C
H
H
OMPM
H
H
O
O O
H
O
OH
14
O
H
15
H
H H Me
O
O
O
HO
H H
(+)-Macquarimicin A (16)
exhibit selective inhibition of neutral sphingomyelinase
and antiinflammatory activity. Inspired by a series of
enzymatic reactions, 16 Tadano and co-workers achieved
the total synthesis of (+)-macquarimicin A (Scheme 3) by
implementing a late stage TADA reaction to assemble
three of the four rings found in the natural product. The
acyclic polyene precursor to the macrocycle was
assembled via a Stille reaction of an (E)-vinyliodide and a
(Z)-vinylstannane. The 17-membered macrocycle was
e
(15) Evans, D. A.; Starr, J. T. Angew. Chem. Int. Ed. 2002, 41, 1787.
(16) Munakata, R.; Katakai, H.; Ueki, T.; Kurosaka, J.; Takao, K.;
Tadano, K. J. Am. Chem. Soc. 2003, 125, 14722.
closed by an intramolecular Tsuji-Trost reaction. Under
thermal conditions, 14 underwent TADA smoothly to
form a single diastereomer without event. The E,Z
geometry of the diene (14) is most likely the origin of
the spectacular endo-selectivity, 17 as only one endo
transition state is free of steric and transannular
interactions. Tadano and co-workers further elaborated
Scheme 4. Synthesis of (+)-Macquarimicin B & C.
(+)-16
Me
H
HO
O
O
MeO
H
H
O
OH
H
Me
Me
H
(+)-Macquarimicin B (18)
O
MeO
Me
H
O H
H
O
CSA
O
OH
17
H
Me
H
H
Me
O
O
O
O
O
H
H
H
H
Me
H
O
(+)-Macquarimicin C (19)
16 (Scheme 4) via an intermolecular hetero-DA reaction
via transcient pentacyclic intermediate 17 to afford (+)macquarimicin
B (18). Furthermore, treatment of 18 with
CSA lead to (+)-macquarimicin C (19) via an
intramolecular dehydrative alkylation.
The highly insecticidal spinosyns have attracted much
synthetic attention in the past decade. Notably, total
syntheses of (-)-spinosyn A have been completed by both
Evans 18 and Paquette. 19 The (-)-spinosyn A structure
contains a key 12-membered lactone fused to the 5,6,5cis-anti-trans
carbocyclic ring system. It has been
proposed that the biogenesis of (-)-spinosyn A 20 involves
a late stage TADA followed by a nucleophile induced
transannular Michael cyclization. Recently, Roush and
co-workers, 21 finished (-)-spinosyn A (24, Scheme 5) by
treating 20 with iPr2NEt and LiCl in MeCN expecting
formation of 21, but the macrocyclization conditions in
reality afforded TADA product 22 in 75% isolated yield
as a mixture of diastereomers. Presumably, cycloadduct
e
(17) (a) Dineen, T. A.; Roush, W. R. Org. Lett. 2003, 5, 4725. (b)
Paquette, L. A.; Chang, J.; Liu, Z. J. Org. Chem. 2004, 69, 6441.
(18) Evans, D. A.; Black, W. C. J. Am. Chem. Soc. 1993, 115, 4497.
(19) (a) Paquette, L. A.; Gao, Z.; Ni, Z.; Smith, G. F. J. Am. Chem.
Soc. 1998, 120, 2543. (b) Paquette, L. A.; Collado, I.; Purdie, M. J. Am.
Chem. Soc. 1998, 120, 2553.
(20) (a) Oikawa, H.; Tokiwano, T. Nat. Prod. Rep. 2004, 21, 321.
(b) Kim, H. J.; Pongdee, R.; Wu, Q.; Hong, L.; Liu, H.-W. J. Am. Chem.
Soc. 2007, 129, 14582.
(21) (a) Mergott, D. J.; Frank, S. A.; Roush, W. R. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 11955. (b) Winbush, S. A.; Mergott, D. J.;
Roush, W. R. J. Org. Chem. 2008, 73, 1818.

22 arose from the tandem macrocyclization-TADA
process with good selectivity, which was driven by the
Scheme 5. The TADA in the synthesis of (-)-Spinosyn A.
Rham
O
RhamO
RhamO
H
Br
steps
Br
Br
21
O
20
O
O
Me
O
P
O
OPMB
Et
(OEt)2
Me OPMB
O
O
Et H
O
iPr2NEt, LiCl
MeCN, 23°C
OPMB
Me
Rham
Me
O
O
Me3P
O
O Et
H
H H
22
Br
23
Me
O
O
Me
OMe
OMe Me
O O
O
O
O
O Et
H H
(-)-SpinosynA (24)
75%
(ds = 73:12:9:6)
OPMB
O
O
O
NMe2
Me
conformational preference of the C6-brominated
macrocycle in the TADA. The division of the remaining
15-membered macrocycle to complete the tetracyclic core
was achieved via a transannular vinylogous Morita-
Baylis-Hillman reaction to afford cycloadduct 23.
Installation of the forosamine unit completed (-)-spinosyn
A in 31 linear steps in a three percent overall yield from
readily available materials.
(+)-Superstolide A (28) is a member of a class of
structurally unique macrolides isolated from Neosiphomia
superstes. 22 The superstolides exhibit highly cytotoxic
activity toward a number of cancer cell lines including
murine P388 leukemia cells. Roush 23 and co-workers’
critical step in the synthesis of 28 (Scheme 6) was a late
stage TADA used to segment the 24-membered
macrocycle into the tricyclic core of the natural product.
Treatment of 25 with Pd(PPh3)4 and TlOEt realized an
e
(22) (a) D’Auria, M. V.; Debitus, C.; Paloma, L. G.; Minale, L.;
Zampella, A. J. Am. Chem. Soc. 1994, 116, 6658.
(23) Tortosa, M.; Yakelis, N. A.; Roush, W. R. J. Am. Chem. Soc.
2008, 130, 2722
(24) Balskus, E. P.; Jacobsen, E. N. Science, 2007, 317, 1736.
Et
intramolecular Suzuki-Miyaura coupling to afford the 24-
membered macrocyle. Macrocycle 26 underwent a highly
Scheme 6. The Roush Synthesis of (+)-Superstolide A.
TBDPSO
MeO
25
TBDPSO
O
O
B
I
Me
Me
O
Me O
O
Me
O
Me
O
Me
MeO
Me
Me
O
26
Me
Me Me
Me
NBoc
NBoc
TBDPSO
H
Me
Me
Me
MeO O
H
NBoc
O
27
Me Me
Me
O
Suzuki
80°C, 2 h,
toluene
steps
NH2OCO
H
Me
Me
Me
MeO
H
OH
NHAc
O
(+)-Superstolide A (28)
Me Me
Me
O
regio- and diastereoselective TADA reaction to yield 27
as the only observed cycloadduct. Moreover, this
example reinforces Deslonchamps conclusions that the
conformation of the macrocycle in the transition state,
which is governed by transannular and electronic
interactions, dictates the product outcome in the TADA.
Sequential treatment of 27 with TBAF, trichloroacetyl
isocyanate, and removal of the acetonide and Boc
protecting groups, followed by an acylation of the
primary amine afforded the desired product, (+)superstolide
A (28).
These examples verify the power of the TADA to
generate complex arrays of densely populated cyclic
structures, which is the most significant feature of this
methodology. Future work on the TADA most likely will
include the development of ligand-controlled highly
enantio- and diastereoselective variants 24 and potentially
tandem TADA/1,3-dipolar cycloaddition reactions to
generate highly functionalized heterocyclic arrays. As
natural product targets become more complex, one should
expect to see the full potential of the TADA unveiled.