Highly regioselective diels-alder reactions toward oroidin alkaloids: Use of a tosylvinyl moiety as a nitrogen masking group with adjustable electronics

Article abstract of DOI:10.1021/ol0473602

(Chemical Equation Presented) The use of the p-toluenesulfonyl (Ts) and tosylvinyl (Tsv) groups as nitrogen masking groups imparted high regioselectivity in Diels-Alder reactions directed toward members of the oroidin-derived marine alkaloid family. The e

Full text of DOI:10.1021/ol0473602

ORGANIC
LETTERS
2005
Vol. 7, No. 9
1679-1682
Highly Regioselective Diels−Alder
Reactions toward Oroidin Alkaloids:
Use of a Tosylvinyl Moiety as a
Nitrogen Masking Group with Adjustable
Electronics
Paul J. Dransfield, Shaohui Wang, Anja Dilley,† and Daniel Romo*
Department of Chemistry, Texas A&M UniVersity, P.O. Box 30012,
College Station, Texas 77843-3012
romo@mail.chem.tamu.edu
Received December 22, 2004
ABSTRACT
The use of the p-toluenesulfonyl (Ts) and tosylvinyl (Tsv) groups as nitrogen masking groups imparted high regioselectivity in Diels−Alder
reactions directed toward members of the oroidin-derived marine alkaloid family. The electron-withdrawing Tsv group was utilized as an
electronically adjustable nitrogen-protecting group as subsequent hydrogenation provided the more electron-rich tosylethyl (Tse) group. This
electronic adjustment strategy avoided a protecting group exchange and provided the required electronics for the key chlorination/ring-
contraction sequence.
The development of protecting groups for organic synthesis
that more precisely control chemoselectivity continues to
drive new advances. However, recent reports demonstrate
the potential of additional utility for protecting groups. For
example, the recent development of the p-nitrobenzenesulfo-
nyl group (nosyl) by Fukuyama illustrates a new direction
toward the development of protecting groups with dual roles
including facilitating removal and altering reactivity, e.g.,
for nitrogen alkylation via Mitsunobu processes.1 Protecting
groups that alter the reactivity and sometimes regioselectivity
of substrates have proven useful for a variety of reactions
including Diels-Alder reactions and electrophilic aromatic
substitution (e.g., acyl groups on phenols or anilines). In our
ongoing studies2 toward the synthesis of oroidin-derived
alkaloids,3 we faced a situation that required the development
of a nitrogen-protecting group with readily adjustable
electronic properties. Herein, we describe an application of
the electron-poor p-tosylvinyl (Tsv) group that is readily
converted to the more electron-rich p-tosylethyl (Tse) group.4
This strategy was applied to our Diels-Alder/chlorination/
ring contraction approach to the oroidin alkaloids,2a in
particular the palau’amines (2-4)5 and the axinellamines (8-
11) (Figure 1).6
(2) (a) Dilley, A. S.; Romo, D. Org Lett. 2001, 3, 1535. (b) Poullennec,
K.; Romo, D. Org. Lett. 2002, 4, 2645. (c) Poullennec, K.; Romo, D. J.
Am. Chem. Soc. 2003, 125, 6344.
(3) For a recent review of oroidin-derived alkaloids, see: Hoffmann,
H.; Lindel, T. Synthesis 2003, 12, 1753.
(4) For a lead reference to the use of the Tse group for nitrogen protection
including conditions for its removal, see: Dastrup, D. M.; Yap, A. H.;
Weinreb, S. M.; Henry, J. R.; Lechleiter, A. J. Tetrahedron 2004, 60,
90.
(5) (a) Kinnel, R. B.; Gehrken, H.-P.; Scheuer, P. J. J. Am. Chem. Soc.
1993, 115, 3376. (b) Kinnel, R. B.; Gehrken, H.-P.; Swali, R.; Skoropowski,
G.; Scheuer, P. J. J. Org. Chem. 1998, 63, 3281.
† Current address: Wyeth Research, CN-8000, Princeton, NJ 08543.
(1) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353.
10.1021/ol0473602 CCC: $30.25
© 2005 American Chemical Society
Published on Web 04/05/2005

Scheme 1. “Biomimetic” Synthesis of the Diastereomeric
Spirocyclic Core Found in the Axinellamines and Palau’amine2a
the Diels-Alder process gave predominantly the desired
regioisomer 14 (4.3:1 ratio, 14/15) with concomitant double-
bond isomerization, we sought to improve the regioselectivity
by altering the electronics of the nitrogen-protecting groups
on the diene. Attempts to improve regioselectivity by
use of Lewis acids were unsuccessful due to the instability
of diene 12 to acid. Optimal yields were obtained without
Lewis acid and with 2,6-lutidine added to scavenge adventi-
tious acid.
We reasoned that use of an electron-withdrawing group
on N1 while maintaining an electron-donating group on N2
would perturb the orbital coefficients of the diene leading
to improved regioselectivity (Figure 2). This analysis prompted
Figure 1. Structure of oroidin and oroidin-derived sponge alkaloids.
Several groups have described synthetic approaches to the
axinellamines and palau’amines including those of Overman,7
Carreira,8 Lovely,9 and Austin.10 Our synthetic approach to
this class of bisguanidine alkaloids is based on the biosyn-
thetic hypothesis proposed by Kinnel and Scheuer.5a,11 Al-
Mourabit and Potier13 and most recently Baran have posited
alternative biosynthetic proposals.12 These metabolites are
thought to be biosynthesized from a common precursor,
oroidin 1.3,13 In our synthetic strategy, a key Diels-Alder/
oxidation/tandem chlorination-1,2-shift sequence resulted
in a four-step enantioselective assembly of the densely
functionalized spirocyclic core 16 from benzyl-protected
vinyl imidazolone 12 and lactam 13 (Scheme 1).2a While
Figure 2. Electronics of vinyl imidazolones as dienes.
(6) (a) Urban, S.; Leone, P. D. A.; Carroll, A. R.; Fechner, G. A.; Smith,
J.; Hooper, J. N. A.; Quinn, R. J. J. Org. Chem. 1999, 64, 731. (b) The
same name was previously given to a simpler pyrrole alkaloid; see:
Bascombe, K. C.; Peter, S. R.; Tinto, W. F.; Bissada, S. M.; McLean, S.;
Reynolds, W. F. Heterocycles 1998, 48, 1461.
(7) (a) Overman, L. E.; Rogers, B. N.; Tellow, J. E.; Trenkle, W. C. J.
Am. Chem. Soc. 1997, 119, 7159. (b) Belanger G.; Hong F.-T.; Overman,
L. E.; Rogers, B. N.; Tellow, J. E.; Trenkle, W. C. J. Org. Chem. 2002, 67,
7780. (c) Katz, J. D.; Overman, L. E. Tetrahedron 2004, 60, 9559.
(8) Starr, J. T.; Koch, G.; Carreira, E. M. J. Am. Chem. Soc. 2000, 122,
8793.
(9) (a) Lovely, C. J.; Du, H.; Dias, H. V. R. Org. Lett. 2001, 3, 1319.
(b) Lovely, C. J.; Du, H.; Dias, H. V. R Heterocycles 2003, 60, 1. (c) He,
Y.; Chen, Y.; Wu, H.; Lovely, C. J. Org. Lett. 2003, 5, 3623.
(10) Koenig, S. G.; Miller, S. M.; Leonard, K. A.; Lowe, R. S.; Chen,
B. C.; Austin, D. J. Org. Lett. 2003, 5, 2203.
(11) This biosynthetic proposal was suggested by a reviewer of the
manuscript by Kinnel and Scheuer (ref 5a).
us to study the p-toluenesulfonyl (Ts) group as an electron-
withdrawing group for N1 and a 3,4-dimethoxybenzyl (DMB)
group14 as an electron-rich group on N2 leading to diene 17
(Scheme 2). This diene was prepared in an analogous manner
to the dibenzylated diene described previously.2a,15 Subse-
quent Diels-Alder reaction of this diene with lactam 13
under thermal conditions resulted in the formation of two
compounds. Further prolonged heating at slightly elevated
temperatures (114 °C) indeed led to the isolation of a single
regioisomer 19 in 75% yield (Scheme 2). Thus, the tosyl
group at N1 had perturbed the orbital coefficients of the diene
(12) Baran, P. S.; O’Malley, D. P.; Zografos, A. L. Angew. Chem., Int.
Ed. 2004, 43, 2674.
(13) (a) Mourabit, A. A.; Potier, P. Eur. J. Org. Chem. 2001, 237.
(14) Difficulties in removing the benzyl group under mild conditions in
similar substrates led to the use of the 3,4-dimethoxybenzyl group.
(15) See the Supporting Information for details.
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Org. Lett., Vol. 7, No. 9, 2005

However, we considered the use of an electron-withdrawing
group (EWG) that in a subsequent transformation could be
converted to a more electron-rich group. In this regard, we
envisioned the use of a tosylvinyl (Tsv) group20 that, in a
vinylogous manner, would approximate the electron-
withdrawing nature of a tosyl group essential for a regiose-
lective Diels-Alder reaction (Scheme 3). Subsequent olefin
Scheme 2. Improved Regioselectivity in the Diels-Alder
Reaction with Diene 17 and Subsequent Transformationsa
Scheme 3. Tsv Group as an Electronically Adjustable
Nitrogen Protecting Group
reduction would yield a tosylethyl (Tse) protecting group21
that would serve as a more electron-rich group determined
to be necessary for the chlorination/ring contraction sequence.
One concern in this strategy was the possibility that the Tsv
group would participate as a dienophile.
Synthesis of the required diene 29 began with the methyl
ester 24b obtained by methylation of the known imidazolone
24a (Scheme 4).2a (Z)-1,2-Di-p-toluenesulfonylethylene22 was
a Reagents and conditions: (a) 2,6-lutidine, 95 °C, 2 d (75%);
(b) DMAP, Et3N, CH2Cl2, (93%); (c) CH2Cl2, MgSO4, -45 °C,
then Me2S, (99%).
Scheme 4. Synthesis of the Tsv-Protected Dienea
allowing for a highly regioselective Diels-Alder process.
The second product was the initial Diels-Alder adduct 18
(i.e., prior to alkene isomerization), which had not been
previously observed. This adduct could be isolated and
independently converted to alkene 19 by prolonged heating.16
Oxidation of alkene 19 to allylic alcohol 21 proceeded in
high yield but in this case17 required the use of trifluorodim-
ethyl dioxirane.18 This is presumably due to the electron-
withdrawing Ts group that rendered the olefin less nucleo-
philic. However, attempts to effect the subsequent chlorination
were unsuccessful using a range of chlorinating reagents in-
cluding NCS, chloramine-T, sodium hypochlorite, 2,3,4,5,6,6-
hexachlorocyclohexa-2,4-dien-1-one, and chlorine gas. The
major product isolated from these reactions was the aroma-
tized product 23.19
a Reagents and conditions: (a) MeOH (60%); (b) NaH, DMF,
20 °C, 15 h; (c) K2CO3, DMF, 60 °C, (56% over two steps); (d)
THF/H2O, 20 °C; (e) THF, cat. DMF, 25 °C; (f) THF, -78 °C
(96% over three steps); (g) CH2Cl2, 25 °C (82%); (h) THF, NaH;
(i) THF/H2O (3/1, v/v), 20 °C; (j) THF, Et3N, 0 °C; (k) THF, -78
°C (77% over four steps).
These observations indicate that an electron-withdrawing
group on N1 benefits the regiochemical outcome of the
Diels-Alder reaction, while the subsequent chlorination/1,2-
shift requires a more electron-rich group on N1. Generally,
this situation would require a protecting group switch.
used to install the Tsv group at the more accessible nitrogen
(N1) via a presumed addition-elimination (-Ts) process.
Protection of N2 with DMB chloride gave the bis-protected
imidazolone ester 25 in 56% overall yield for the two steps.
Attempts to selectively reduce ester 25 to alcohol 27 using
DIBALH were unsuccessful leading to concomitant reduction
of the Tsv alkene. A more lengthy but high-yielding sequence
(16) Lovely has observed related alkene isomers in similar Diels-Alder
reactions employing vinyl imidazoles (see ref 9a).
(17) Oxidation of the dibenzylated adduct 14 could be achieved in nearly
quantitative yield with dimethyl dioxirane (see ref 2a).
(18) Mello, R.; Fiorentino, M.; Sciacovelli, O.; Curci, R. J. Org. Chem.
1988, 53, 3890.
(19) Since this 1,2-shift proceeds through an electron-poor, three-centered,
two electron transition state, it appears that elimination processes leading
to aromatized product 23 become competitive with the desired 1,2-shift.
(20) To the best of our knowledge, the use of the Tsv group as a
protecting group has not been described in the literature.
Org. Lett., Vol. 7, No. 9, 2005
1681

involving hydrolysis to the acid, acid chloride formation, and
reduction with lithium borohydride gave alcohol 27 in 96%
overall yield for the three steps. Oxidation proceeded
smoothly to give the corresponding aldehyde in 82% yield.
Following olefination, a three-step sequence was again
required to prevent reduction of the Tsv group. Horner-
Wadsworth olefination, hydrolysis of the ester, mixed
anhydride formation, and treatment with LiBH4 provided
dienyl alcohol 29 in 77% yield over the four steps. The
synthesis of diene 29 is lengthy but requires no purification
by column chromatography throughout the 10-step sequence
from ester 24b. Instead, acid-base extractions were used to
purify the intermediate carboxylic acids.
adduct from the Tse-protected diene 3023 and subsequent
alcohol protection. Comparison by 1H and 13C NMR verified
that the same cycloadduct had been obtained by the two
routes.
A two-stage oxidation/rearrangement as described previ-
ously2a provided the cyclopentane 35. Oxidation of the Tse-
protected Diels-Alder adduct 33 provided the allylic alcohol
34 in nearly quantitative yield. Subsequent treatment with
NCS resulted in the formation of the aromatized product (cf.
23) as the major product. However, treatment with chloram-
ine-T at low temperature minimized formation of the
aromatized product providing cyclopentane 35 as the major
product.
Heating diene 29 with dienophile 13 in benzene in a sealed
tube at 95 °C pleasingly led to the formation of a single
regioisomeric, Diels-Alder adduct 31 in 48% overall yield
following protection of the alcohol as the TBDPS ether
(Scheme 5). Similar results were obtained using microwave
In summary, strategies leading to improved regioselectivity
were designed and implemented for the key Diels-Alder
process toward the oroidin alkaloids axinellamine and
palau’amine. One strategy entailed the use of an electroni-
cally adjustable protecting group to circumvent the need for
a cumbersome and potentially difficult protecting group
switch. While the efficiency of the Diels-Alder process
using the Tsv-protected diene is not fully optimized, we
anticipate that the concept of an electronically adjustable
protecting group may find wider application in organic
synthesis. The advanced spirocyclopentane 35 is a serviceable
intermediate in our projected total synthesis of the axinel-
lamines, and the results of these studies will be reported in
due course.
Scheme 5. Diels-Alder Reactions and the Oxidation/
Chlorination/Rearrangement Processa
Acknowledgment. We thank the NIH (NIGMS 52964),
the Welch Foundation (A-1280), and Pfizer for support of
these investigations. D.R. is an Alfred P. Sloan Fellow
and a Camille Dreyfus Teacher-Scholar. The NSF (CHE-
0077917) provided funds for purchase of NMR instrumenta-
tion.
Supporting Information Available: Selected experi-
1
mental procedures and characterization data (including H
and 13C NMR spectra) for compounds 17, 19, 21, 25, 27,
29-31, 33, 35-40, 44, and 47-50. This material is available
free of charge via the Internet at http://pubs.acs.org.
a Reagents and conditions: (a) 2,6-lut, 95 °C, sealed tube; (b)
Et3N, DMAP, CH2Cl2, 24 h, 25 °C (48% of 33 based on 13,
2 steps; 48% of 31 based on 13, 2 steps); (c) EtOAc, 25 °C (93%);
(d) CH2Cl2, -50 °C; DMS (99%); (e) CH2Cl2, -50 f 25 °C (65%).
OL0473602
(21) The Tse group has had limited use; a partial reference list includes:
(a) Faubl, H. Tetrahedron Lett. 1979, 491. (b) Gonzalez, C.; Greenhouse,
R.; Tallabs, R.; Muchowski, J. M. Can J. Chem. 1983, 61, 1697. (c) Rao,
A. K. S. B.; Rao, C. G.; Singh, B. B. Synth. Commun. 1994, 24, 341. (d)
DiPietro, D.; Borzilleri, R. M.; Weinreb, S. M. J. Org. Chem. 1994, 59,
5856. (e) Borzilleri, R. M.; Weinreb, S. M.; Parvez, M. J. Am. Chem. Soc.
1995, 117, 10905. (f) Artman, G. D., III; Walman, J. H.; Weinreb, S. M.
Syntheis 2002, 2057. (g) Bashford, K. E.; Cooper, A. L.; Kane, P. D.;
Moody, C. J. Tetrahedron Lett. 2002, 43, 135. (h) Dastrup, D. M.; Yap, A.
H.; Weinreb, S. M.; Henry, J. R.; Lechleiter, A. J. Tetrahedron 2004, 60,
901 and references cited within.
(22) (a) Snyder, H. R.; Hallada, D. P. J. Am. Chem. Soc. 1952, 74, 5.
(b) Cossu, S.; De Lucchi, O.; Durr, R.; Fabris, F. Synth. Commun. 1996,
26, 211.
(23) This diene was prepared by an analogous procedure as for diene 17
employing the mesylate of â-tosylethanol for N1 protection (see the
Supporting Information for details). This diene provided a 2.5:1 ratio of
Diels-Alder regioisomers, with the major product being the desired
regioisomer.
irradiation at 175 °C for 45 min. In agreement with previous
studies, the double bond had isomerized to regenerate the
imidazolone ring under the reaction conditions. An additional
product isolated was tentatively assigned the structure
resulting from competing dimerization of the diene in which
the Tsv group had served as a dienophile. Selective reduction
of the Tsv olefin of tricycle 31 was readily accomplished
by hydrogenation to yield the Tse-protected adduct 33 in
near-quantitative yield. Corroboration of this structure was
obtained by independent synthesis of the same Diels-Alder
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Org. Lett., Vol. 7, No. 9, 2005