Asymmetric total synthesis of the 1-epi-aglycon of the cripowellins A and B

Article abstract of DOI:10.1021/jo0518093

The unusual [5.3.2]-bicyclic structure of the insecticidal Amaryllidaceae alkaloids cripowellin A (1) and B (2) has been synthesized for the first time via a sequence of Sharpless dihydroxylation, ring-closing metathesis, and intramolecular Heck reaction. The asymmetric synthesis of the 1-epi-aglycon 82 proceeds with virtually complete diastereo- and enantioselectivity (de, ee ≥ 98%) in 13 steps and an overall yield of 5.6%. In addition, three alternative approaches toward the aglycon 3 are also described focusing on (1) the alkylation of the 2-benzazepinedithianes 35 and 36 with the electrophile 11, (2) a radical cyclization of the precursor (R/S,S,S)-39, and (3) an intramolecular arylation reaction of the aryl ketone 47.

Full text of DOI:10.1021/jo0518093

Asymmetric Total Synthesis of the 1-epi-Aglycon of the
Cripowellins A and B
Dieter Enders,* Achim Lenzen, Michael Backes, Carsten Janeck, Kelly Catlin,
Marie-Isabelle Lannou, Jan Runsink, and Gerhard Raabe
Institut fu¨r Organische Chemie, RWTH Aachen, Landoltweg 1, 52074 Aachen, Germany
enders@rwth-aachen.de
Received August 27, 2005
The unusual [5.3.2]-bicyclic structure of the insecticidal Amaryllidaceae alkaloids cripowellin A
(1) and B (2) has been synthesized for the first time via a sequence of Sharpless dihydroxylation,
ring-closing metathesis, and intramolecular Heck reaction. The asymmetric synthesis of the 1-epi-
aglycon 82 proceeds with virtually complete diastereo- and enantioselectivity (de, ee g 98%) in 13
steps and an overall yield of 5.6%. In addition, three alternative approaches toward the aglycon 3
are also described focusing on (1) the alkylation of the 2-benzazepinedithianes 35 and 36 with the
electrophile 11, (2) a radical cyclization of the precursor (R/S,S,S)-39, and (3) an intramolecular
arylation reaction of the aryl ketone 47.
Introduction
The alkaloids isolated from different species in the
Amaryllidaceae plant family certainly represent a unique
class among the alkaloids because they have been found
to occur only in this family.1 Conversely, alkaloids of
other plant families have not been found in the Amaryl-
lidaceae (with hordenin being the only exception).2 So far,
about 200 alkaloids have been identified, and their often
interesting pharmacological properties along with their
fascinating molecular structures have rendered them
very popular targets for total synthesis.
In 1997, researchers of Bayer AG reported two new
Amaryllidaceae alkaloids, cripowellin A (1) and B (2)
(Figure 1), which were isolated from bulbs and roots of
Crinum powellii, a popular ornamental plant in Eu-
rope.3,4 Their structures were determined by extensive
FIGURE 1. Structures of the cripowellins A (1) and B (2).
spectroscopic studies, including a combination of MS and
1-D and 2-D NMR techniques. The relative configuration
was assigned unambiguously by an X-ray crystallo-
graphic analysis of cripowellin A diacetate. Both cripo-
wellins are glycosides whose common aglycon features a
[5.3.2]-bicyclic core, an unprecedented structural motif
among the Amaryllidaceae alkaloids. Although both
sugar entities differ from each other significantly, with
an unusual 1,3,5-trioxepane ring in the case of cripo-
wellin A (1), it is reasonable to assume that they are
derived biogenetically from â-D-glucose, which accounts
for the depicted absolute configuration.
(1) For representative reviews about the Amaryllidaceae alkaloids,
see: (a) Hoshino, O. In The Alkaloids; Cordell, G. A., Ed.; Academic
Press: New York, 1998; Vol. 51, pp 324-424. (b) Martin, S. F. In The
Alkaloids; Brossi, A., Ed.; Academic Press: New York, 1987; Vol. 30,
pp 251-376. (c) Fuganti, C. In The Alkaloids; Manske, R. H. F., Ed.;
Academic Press: London, 1975; Vol. 15, pp 83-164.
(2) Wildman, W. C. In Chemistry of the Alkaloids; Pelletier, S. W.,
Ed.; Van Nostrand Reinhold Co.: New York, 1970; pp 151-172.
(3) Gehling, M. et al. (Bayer AG), DE 196 10 279 A1, 1997; Chem.
Abstr. 1997, 127, 278406.
(4) Velten, R.; Erdelen, C.; Gehling, M.; Go¨hrt, A.; Gondol, D.; Lenz,
J.; Lockhoff, O.; Wachendorff, U.; Wendisch, D. Tetrahedron Lett. 1998,
39, 1737-1740.
In addition to their unusual structure, both alkaloids
exhibit extraordinary insecticidal activity comparable to
10.1021/jo0518093 CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/12/2005
10538
J. Org. Chem. 2005, 70, 10538-10551

1-epi-Aglycon of the Cripowellins A and B
SCHEME 1. Retrosynthesis I with the Alkylation
of the 2-Benzazepine Dithiane 5 as the Key Step
In the first step, a retro-lactamization of aglycon 3 was
considered, giving the partially protected amino acid 4.
We presumed that its synthesis should be possible in a
rather straightforward manner by alkylation of the
dithiane 510 with either one of the electrophiles of type
A or B. For the synthesis of the desired dithiane 5, two
different routes, a and b, were envisaged utilizing a
lactamization-reduction sequence and a Pictet-Spengler
reaction, respectively. Synthon 8 may be obtained by
simple alkylation or aminoethylation11 of the (R)-1-amino-
2-methoxymethyl pyrrolidine (RAMP) hydrazone12 of
homopiperonal (9). The benzylic stereocenter of 6 could
be developed using the RAMP hydrazone methodology.
However, its synthesis starting from 6-bromopiperonylic
amine 7 was expected to be more laborious.
1.1. Synthesis of Electrophilic A- and B-Type
Components. The synthesis of electrophiles of type A
and B is summarized in Scheme 2. The iodides 11 and
13 were prepared from their corresponding alcohols 1013
and 1214 by simple iodination reactions (PPh3, imidazole,
I2). The synthesis of 17 began from D-tartaric acid (14),
which furnished the cyclic anhydride 15 after treatment
with pivaloyl chloride. A two-step sequence of reduction
and acid-catalyzed lactonization converted 15 to the
γ-lactone 16, which was reacted with TMSBr in methanol
to afford the bromide 17.
that of natural pyrethroidssnot only with regard to its
potency but also its broad activity. In this respect, it is
noteworthy that the aglycon seems to be mainly respon-
sible for their biological activity because it shows the
same degree of activity as the two glycosides themselves.4
However, practically nothing is known about the mode
of action.5 To clarify that aspect and to perform investi-
gations on structure-activity relationships, the synthesis
of stereoisomers and derivatives of the cripowellins will
be necessary.
Due to their unique structures and their high biological
activity, Bayer AG has patented them and some of their
derivatives.3 Their exceptional position was also recog-
nized by experts at the Irseer conference about natural
products in 1997 where cripowellin A (1) was chosen to
be the “second most interesting new natural product”.6
Despite this attention, a synthetic approach toward the
cripowellins or derivatives had not been reported until
very recently when we described the asymmetric syn-
thesis of the 1-epi-aglycon.7 Similarly, Moon et al. re-
cently demonstrated an alternative approach leading to
the racemic bisdeoxy-aglycon of the cripowellins.8
During the course of our work, originally directed
toward the synthesis of the “natural” aglycon, a number
of conceptually different approaches were investigated,
one of which delivered the 1-epi-aglycon. In the present
paper, we report full details of these efforts.9
Monobenzylation of the diol 1815 gave the alcohol 19,
which was further transformed into the iodide 20 using
conditions similar to those described for 10 and 12 (vide
supra).
1.2. Synthesis of 2-Benzazepine Dithianes: Route
a. Investigations describing route a are summarized in
Scheme 3. With respect to the nitrogen-protecting groups,
two different pathways are shown, both commencing with
6-bromopiperonylic amine 7.16
Two different protecting groups for the nitrogen atom,
a p-methoxybenzyl and a benzyl group, were introduced
successively to give 21. After bromine-lithium exchange,
the lithium species was trapped with DMF to obtain the
aromatic aldehyde 22. A sequence consisting of a Wittig
reaction with Ph3PCHOCH3 and hydrolysis of the inter-
mediate enol ether furnished the corresponding homolo-
gated aldehyde, which was reacted with RAMP to give
the hydrazone 23. Disappointingly, the alkylation of 23
with methyl 2-bromoacetate under standard conditions
proceeded only in moderate yield and with an unsatisfac-
tory degree of diastereoselectivity.
(10) A conceptually different route to the racemic dithianes 5 with
R1 ) Cbz, H has already been described: Sa´nchez, I. H.; Soria, J. J.;
Lo´pez, F. J.; Larraza, M. I.; Flores, H. J. J. Org. Chem. 1984, 49, 157-
163.
(11) Enders, D.; Janeck, C. F.; Raabe, G. Eur. J. Org. Chem. 2000,
3337-3345.
(12) For reviews about the SAMP/RAMP-hydrazone methodology in
asymmetric synthesis, see: (a) Enders, D. In Asymmetric Synthesis;
Morrison, J. D., Ed.; Academic Press: Orlando, 1984; Vol. 3, pp 275-
339. (b) Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D.
Tetrahedron 2002, 58, 2253-2329. (c) Enders, D.; Voith, M.; Lenzen,
A. Angew. Chem. 2005, 117, 1330-1351; Angew. Chem., Int. Ed. 2005,
44, 1304-1325.
(13) Hungerbu¨hler, E.; Seebach, D. Helv. Chim. Acta 1981, 64, 687-
702.
(14) (a) Batsanov, A. S.; Begley, M. J.; Fletcher, R. J.; Murphy, J.
A.; Sherburn, M. S. J. Chem. Soc., Perkin Trans. 1 1995, 1281-1294.
(b) Musich, J. A.; Rapoport, H. J. Am. Chem. Soc. 1978, 100, 4865-
4872.
(15) Haag, D.; Scharf, H.-D. J. Org. Chem. 1996, 61, 6127-6135.
(16) Clark, P. W.; Dyke, S. F. J. Organomet. Chem. 1985, 281, 389-
396.
Results and Discussion
1. Dithiane-Alkylation Approach. Our initial ret-
rosynthetic analysis of the aglycon 3 of the cripowellins
A (1) and B (2) is outlined in Scheme 1.
(5) Researchers at Bayer AG have found out that cripowellin A and
B are neither acetylcholin esterase inhibitors nor PP1 inhibitors.
(6) Lindel, T. Nachr. Chem. Technol. Lab. 1997, 45, 775-779.
(7) Enders, D.; Lenzen, A.; Raabe, G. Angew. Chem. 2005, 117,
3832-3835; Angew. Chem., Int. Ed. 2005, 44, 3766-3769.
(8) Moon, B.; Han, S.; Yoon, Y.; Kwon, H. Org. Lett. 2005, 7, 1031-
1034.
(9) (a) Catlin, K. RWTH Aachen, unpublished results. (b) Janeck,
C. F., Ph.D. Thesis, RWTH Aachen, 2000. (c) Backes, M., Ph.D. Thesis,
RWTH Aachen, 2004. (d) Lenzen, A., Ph.D. Thesis, RWTH Aachen,
2005.
J. Org. Chem, Vol. 70, No. 25, 2005 10539

Enders et al.
SCHEME 2. Synthesis of A- and B-Type Electrophiles
SCHEME 3. Investigations of Route a of the Retrosynthetic Plan I
We theorized that the combination of two benzyl
protecting groups was probably too bulky, diminishing
the energy difference between the two possible diaster-
eomeric transition states leading to a lower asymmetric
induction in the alkylation. This argument was supported
by the alkylation results from the homopiperonal-RAMP-
hydrazone 30 bearing no ortho substituent (cf. Scheme
4) and from the corresponding (S)-1-amino-2-methoxy-
methylpyrrolidine (SAMP)-hydrazone 27 bearing two
allyl protecting groups on the nitrogen atom (it is
needless to say that we would have replaced SAMP by
RAMP as the chiral auxiliary if we had persued with this
approach since only the latter induces the right asym-
metric induction at the benzylic stereocenter). The syn-
thesis of 27 was carried out according to the preparation
of 23sexcept the benzylic protecting groups were both
replaced by two allyl groups (cf. 7 f 25). Alkylation of
this hydrazone under identical conditions furnished 28,
which now gave superior results in terms of both yield
(88 vs 53%) and stereoselectivity (de ) 90 vs 82%).
Unfortunately, the removal of the allyl protecting
groups proved problematic. Although various standard
reaction conditions for their deprotection had been tested
(Rh(PPh3)3Cl, CH3CN/H2O (9:1);17 Pd(PPh3)4, DCM, tolu-
enesulfinic acid;18 Pd(dba)2/dppb (1:1), THF, 2-mercap-
(17) Laguzza, B. C.; Ganem, B. Tetrahedron Lett. 1981, 22, 1483-
1486.
(18) Honda, M.; Morita, H.; Nagakura, I. J. Org. Chem. 1997, 62,
8932-8936.
10540 J. Org. Chem., Vol. 70, No. 25, 2005

1-epi-Aglycon of the Cripowellins A and B
SCHEME 4. Investigations on Route b of
Retrosynthesis I
SCHEME 5. Dithiane 37 Was Used To Optimize
the Reaction Conditions for Coupling with 11
analysis on a chiral stationary phase (the racemate of
33 was prepared accordingly, starting from the dimeth-
ylhydrazone 29 of homopiperonal). This evidence implied
the absence of racemisation in the transformation of
hydrazone to dithiane. Although we were not able to
prove this for the dithiane 34, it seems reasonable to
make the same assumption.
Dithiane 34 smoothly underwent the Pictet-Spengler
cyclization22 to the 2-benzazepine 36. In this respect, it
is important to note that the hydrazone 32 could not be
cyclized successfully under various conditions, including
formaldehyde, NaOH(aq);11 (CH2O)3 or (CH2O)n, CH3-
SO3H;23 BF3‚OEt2, CH2(OCH3)2;24 and (CH2O)n, TFA.25 In
the case of 33, the corresponding benzyl amide was
initially formed according to the Weinreb protocol.26
Cyclization was then readily conducted as well.24 The
reduction of the resulting lactam with lithium aluminum
hydride yielded the benzyl-protected 2-benzazepine 35.
1.4. Coupling Reactions. With the 2-benzazepine-
dithianes 35 and 36 and various electrophiles 11, 13, 17,
and 20 in hand, model studies with the dithiane 37 were
conducted in order to optimize reaction conditions for the
coupling process (Scheme 5).27
We found out, that only the electrophile 11 could be
reacted successfully with a metalated species of 37. After
screening of different reaction conditions and further
optimization we were finally able to isolate the coupling
product 38 in a moderate yield of 65%.
However, similar alkylations of dithianes 35 and 36
with the electrophile 11 under these conditions were not
feasible. The screening of other electrophiles showed that
only very small electrophiles were amenable to this
reaction with CH3I and D2O resulting in yields of 30%
and 56%, respectively.
2. Intramolecular Radical Cyclization Approach.
The preceding section has shown that a polar, umpolung
disconnection adjacent to the dithiane 5 using the A-/B-
type electrophiles (cf. Scheme 1) did not prove successful.
A radical disconnection adjacent to the carbonyl group
was also envisaged (Scheme 6). The key step in this
approach was the intramolecular radical cyclization from
(S,S,S)-39 to explore addition of the primary carbon
radical to the nitrile group.28 Breaking of the amide bond
tobenzoic acid19), these blocking groups were not removed
in the case of 28.
1.3. Synthesis of 2-Benzazepine Dithianes: Route
b. The desired 2-benzazepinedithianes were synthesized
in a highly stereoselective fashion by utilizing the Pictet-
Spengler reaction as the key step. Scheme 4 outlines the
approaches to the 2-benzazepines with a tosyl or a benzyl
N-protecting group by employing tosylaziridine and
methyl 2-bromoacetate, respectively, as the electrophiles.
The condensation of homopiperonal (9)20 with RAMP
yielded the hydrazone 30, whose alkylation with the
aforementioned electrophiles gave the hydrazones 31 and
32, which were obtained with high diastereoselectivity
(by 13C NMR spectroscopy). Both of these hydrazones
were transformed to the dithianes 33 and 34 according
to Lassaletta’s procedure.21 In the case of 33, the enan-
tiomeric excess was determined to be g98% by HPLC
(22) (a) Kano, S.; Tokumatsu, T.; Yuasa, Y. Heterocycles 1983, 20,
165. (b) Kano, S.; Tokumatsu, T.; Yuasa, Y. Heterocycles 1984, 21, 700.
(23) Orazi, O. O.; Corral, R. A.; Giaccio, H. J. Chem. Soc., Perkin
Trans. 1 1986, 1977-1982.
(24) Watson, T. J. N. J. Org. Chem. 1998, 63, 406-407.
(25) Ishizaki, M.; Ozaki, K.; Kanematsu, A.; Isoda, T.; Hoshino, O.
J. Org. Chem. 1993, 58, 3877-3885.
(26) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977,
18, 4171-4173.
(27) For work on 1,3-dithianes, see: (a) Seebach, D. Synthesis 1969,
17-36. (b) Smith, A. B., III; Adams, C. M. Acc. Chem. Res. 2004, 37,
365-377.
(19) Lemaire-Audoire, S.; Savignac, M.; Geneˆt, J. P.; Bernard, J.-
M. Tetrahedron Lett. 1995, 36, 1267-1270.
(20) Ban, Y.; Oishi, T. Chem. Pharm. Bull. 1958, 6, 574-576.
(21) Die´z, E.; Lo´pez, A. M.; Pareja, C.; Mart´ın, E.; Ferna´ndez, R.;
Lassaletta, J. M. Tetrahedron Lett. 1998, 39, 7955-7958.
(28) For similar work, see: (a) Ziegler, F. E.; Harran, P. G. Synlett
1995, 493-494. (b) Ziegler, F. E.; Harran, P. G. J. Org. Chem. 1993,
58, 2768-2773.
J. Org. Chem, Vol. 70, No. 25, 2005 10541

Enders et al.
SCHEME 6. Retrosynthesis Plan II Featuring an
Intramolecular Radical Cyclization
As one might have anticipated, the presence of the
â-oxygen substituent gave rise to olefinic products of
â-elimination.
The strategies discussed so far had one thing in
common: the characteristic bicycle was planned to be
constructed starting from a 2-benzazepine, i.e., a 7-mem-
bered ring. Alternatively, because a [5.3.2]-bicycle rep-
resents a combination of a 7-, a 9- and a 10-membered
ring, one could also think about closing the 10- or the
9-membered ring first. These two concepts have also been
followed and will be treated in the following two sections.
3. Intramolecular Ketone-Arylation Approach. If
one wants to start with the largest ring, i.e., the 10-
membered ring, the ethylene bridge has to be broken first
retrosynthetically, which is done most easily by a retro-
intramolecular alkylation reaction (Scheme 9). This leads
to the ketone 46, whose synthesis was envisaged to be
realized by means of an intramolecular Buchwald-
Hartwig arylation (47 f 46).32 Origins of compound 47
can be easily traced to the secondary amine 48 and the
acid 49, and the latter can be obtained by reaction of 50
or 11 with 5133 or 52.
SCHEME 7. Synthesis of the Acid 41
Extensive investigations were carried out for the
synthesis of 49 (Scheme 10). Starting with the electro-
philes 50 and 11, utilization of lithiated 1,3-dithiane (52)
as the synthetic equivalent of a formyl anion delivered
53 and 54, respectively. The moderate yields obtained
in these reactions parallel the observations using the
dithianes 35 and 36 (vide supra). The methylation of 53
and 54, on the other hand, proceeded more smoothly to
give 55 and 56, respectively. After cleavage of the
dithiane moiety, the ketones 57 and 58 were obtained in
similar yields.
This reaction sequence was significantly shortened by
using the lithiated aminonitrile 51 as an equivalent of
an acyl anion. Reaction of 50 and 11 with 51 followed by
AgNO3-mediated cleavage of the aminonitrile furnished
57 and 58 in only two steps and with improved yields.
So far, both protecting groups did not behave much
differently, giving similar yields in each pair of reactions.
However, deprotection to the corresponding alcohol 59
proved to be much more efficient with the benzyl deriva-
tive 58 (97% vs 27% yield in the case of the TBS protected
compound 57). The basicity of TBAF might be responsible
for the low yield observed in the reaction with 57:
formation of the internal enol followed by elimination of
the â-oxygen are a possible side reaction. The synthesis
of the desired acid 49 was then completed by oxidation
with RuCl3/NaIO4.
in (S,S,S)-39 leads to the secondary amine (S)-40 and
the acid 41.
As shown in Scheme 7, saponification of the ester 13
using LiOH gave the desired acid 41 in high yield.
The synthesis of the cyclization precursor is depicted
in Scheme 8. Starting from the hydrazone 32 (cf. Scheme
4), magnesium monoperoxyphthalate (MMPP) mediated
nitrile formation furnished 42, which readily underwent
a Pictet-Spengler cyclization in quantitative yield to 43.
Although the toluenesulfonyl protecting group was easily
removed at this stage using sodium naphthalide, the
benzylic nitrile underwent epimerization. Hence, only
racemic (R/S)-40 could be isolated. Despite this fact, we
decided to continue with the synthesis, hoping for a
possibility to separate diastereomers after a successful
cyclization. Among the different conditions tested for
amide bond formation with the acid 41 (2-chloro-1-
methylpyridinium iodide, n-Bu3N, DCM (48% yield);29
Ph2P(dO)OC6F5, Et-i-Pr2N, DMF (85% yield)30), a com-
bination of HOBT/EDC31 worked best to give (R/S,S,S)-
39 in 89% yield.
The radical cyclization of (R/S,S,S)-39 using Bu3SnH/
AIBN in different solvents did not furnish the desired
acetonide aglycon 44, but instead the unreacted starting
material was recovered (when using refluxing benzene
or toluene) or product 45 (when using refluxing xylene)
resulting from a radical dehalogenation was obtained.
Iodine-metal exchange using using t-BuLi, n-BuLi, and
i-PrMgCl with (R/S,S,S)-39 was attempted hoping for
intramolecular nucleophilic addition to the nitrile group.
The completion of the synthesis of the precursor for
the Buchwald-Hartwig arylation is shown in Scheme 11.
Reductive amination of bromopiperonal (60)34 with 2-ben-
zyloxyethanamine35 gave the secondary amine 48. Amide
formation with the carboxylic acid 49 worked best using
2-fluoro-1-ethylpyridinium tetrafluoroborate (FEP)36 as
(32) (a) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119,
11108-11109. (b) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc.
1997, 119, 12382-12383. (c) Culkin, D. A.; Hartwig, J. F. Acc. Chem.
Res. 2003, 36, 234-245. (d) Satoh, T.; Miura, M.; Nomura, M. J.
Organomet. Chem. 2002, 653, 161-166.
(29) Bald, E.; Saigo, K.; Mukaiyama, T. Chem. Lett. 1975, 1163-
1166.
(30) Chen, S.; Xu, J. Tetrahedron Lett. 1991, 32, 6711-6714.
(31) (a) Sheehan, J. C.; Cruickshank, P. A.; Boshart, G. L. J. Org.
Chem. 1961, 26, 2525-2528. (b) Sheehan, J. C.; Preston, J.; Cruick-
shank, P. A. J. Am. Chem. Soc. 1965, 87, 2492-2493. (c) Nozaki, S.;
Muramatsu, I. Bull. Chem. Soc. Jpn. 1982, 55, 2165-2168.
(33) Be´jaud, M.; Mion, L.; Taillades, J.; Commeyras, A. Tetrahedron
1975, 31, 403-410.
(34) Meyers, A. I.; Flisak, J. R.; Aitken, R. A. J. Am. Chem. Soc.
1987, 109, 5446-5452.
(35) Balderman, D.; Kalir, A. Synthesis 1978, 24-26.
10542 J. Org. Chem., Vol. 70, No. 25, 2005

1-epi-Aglycon of the Cripowellins A and B
SCHEME 8. Radical Cyclization Approach
SCHEME 9. Retrosynthesis III Based on an
Intramolecular Ketone Arylation Reaction
A Heck arylation of the corresponding TBS enol ether
62 was also investigated under typical conditions (Pd-
(OAc)2, PPh3, Et3N, DMF, 80 °C; Pd2dba3, Ag2CO3, dppe,
toluene, 100 °C). It should be noted that Heck reactions
employing alkyl enol ethers have been carried out suc-
cessfully,39 although versions using the analogous silyl
enol ethers have not been described. Unfortunately, both
of these reactions failed to yield 46 (Scheme 12).
The main problem seemed to be the cyclization of the
10-membered cycle and not, e.g., the insertion of Pd0 into
the aryl bromine bond. The occurrence of the latter could
be proven by successfully carrying out an intermolecular
version of the Kuwajima-Urabe reaction (Scheme 13):
the Boc-protected amine 63 and the TMS enol ether 64,
obtained by treatment of 57 with TMSOTf and Et3N,
readily underwent the coupling to give 65 in an unopti-
mized yield of 52%.
4. Synthesis of the 1-epi-Aglycon via a Sharpless
AD-RCM-Heck Sequence. From a topological point of
view, the last possibility that remained was to focus on
the formation of the 9-membered ring. Taking this into
account, our new retrosynthesis is depicted in Scheme
14. After the functional group interconversion ketone f
Z-double bond and protection of the free vicinal hydroxy
groups as their acetonide, the bicycle 66 was considered.
Retrosynthetically, the Heck reaction,40 starting from 68,
was assumed to proceed via intermediate 67 which
should furnish 66 upon elimination of L2PdHX. Consider-
ing Bredt’s rule, an elimination toward the aromatic
moiety was judged as rather improbable at the beginning
of this project (vide infra). Such an intramolecular Heck
the coupling reagent to give the desired precursor 47 in
84% yield.
Unfortunately, bringing about the desired cyclization
to 46 using Buchwald’s conditions turned out to be an
extremely difficult task.37 With xantphos as the ligand
and Pd2dba3 as the Pd0 source, no conversion of starting
material or decomposition were observed under the
reaction conditions screened (THF or toluene as solvent,
t-BuONa or K3PO4 as base, ϑ ) rt - 80 °C).
The Buchwald-Hartwig arylation was not the only
possibility that could be envisaged for the cyclization of
47 to 46. The successful synthesis of the corresponding
terminal TMS enol ether 61 suggested the possibility for
cyclization following the protocol developed by Kuwajima
and Urabe,38 i.e., employing aryl bromides in an arylation
of TMS enol ethers using Bu3SnF and PdCl2(P(o-tol)3)2.
(39) See for example: Andersson, C.-M.; Hallberg, A.; Daves, G. D.,
Jr. J. Org. Chem. 1987, 52, 3529-3536.
(40) Representative reviews about the Heck reaction: (a) Bra¨se, S.;
de Meijere, A. In Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.;
de Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004; pp
217-315. (b) Link, J. T.; Overman, L. E. In Metal-Catalyzed Cross-
Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH:
Weinheim, 1998; pp 231-269. (c) Dounay, A. B.; Overman, L. E. Chem.
Rev. 2003, 103, 2945-2963. (d) Link, J. T. Organic Reactions 2002,
60, 157-534. (e) de Meijere, A.; Meyer, F. E. Angew. Chem. 1994, 106,
2473-2506; Angew. Chem., Int. Ed. Engl. 1994, 33, 2379-2411.
(36) Li, P.; Xu, J. C. J. Peptide Res. 2001, 58, 129-139.
(37) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2000, 122, 1360-1370.
(38) Kuwajima, I.; Urabe, H. J. Am. Chem. Soc. 1982, 104, 6831-
6833.
J. Org. Chem, Vol. 70, No. 25, 2005 10543

Enders et al.
SCHEME 10. Studies Leading to the Keto Acid 49
SCHEME 11. Intramolecular Ketone-Arylation
Approach
SCHEME 12. Cyclization Attempts via a Heck or a
Kuwajima Reaction
The synthesis of the acid 71 was straightforward and
is summarized in Scheme 15. It commenced with the
esterification of the known alcohol 7245 to give 73,46 which
was subjected to a slightly modified Sharpless AD.47 This
reaction furnished the diol 74 in good yield (72%) with
reaction involving a 9-membered ring had not been
reported at the time of this project.
Medium-sized rings, as described for the conversion of
68 to 69, are sometimes very difficult to access by ring-
closing metathesis.41 We tried to advance our strategy
by choosing the acetonide as protecting group because it
represents a conformational constraint that should favor
the RCM process.42,43 Similarly, the tertiary amide func-
tionality should have the same effect.44
(42) For the metathetic synthesis of 9-membered rings using similar
conformational constraints to the dioxolane ring, see: (a) Harris, P.
W. R.; Brimble, M. A.; Gluckman, P. D. Org. Lett. 2003, 5, 1847-1850.
(b) Clark, J. S.; Marlin, F.; Nay, B.; Wilson, C. Org. Lett. 2003, 5, 89-
92. (c) Kaliappan, K. P.; Kumar, N. Tetrahedron Lett. 2003, 44, 379-
381. (d) Hirama, M.; Oishi, T.; Uehara, H.; Inoue, M.; Maruyama, M.;
Oguri, H.; Satake, M. Science 2001, 294, 1904-1907. (e) Clark, J. S.;
Hamelin, O. Angew. Chem. 2000, 112, 380-382; Angew. Chem., Int.
Ed. 2000, 39, 372-374. (f) Bamford, S. J.; Goubitz, K.; van Lingen, H.
L.; Luker, T.; Schenk, H.; Hiemstra, H. J. Chem. Soc., Perkin Trans.
1 2000, 345-351. (g) Oishi, T.; Nagumo, Y.; Hirama, M. Chem.
Commun. 1998, 1041-1042. (h) Delgado, M.; Mart´ın, J. D. Tetrahedron
Lett. 1997, 38, 6299-6300.
(43) There are only very few examples for the metathetic synthesis
of 9-membered rings without conformational constraints. They are
limited almost exclusively to those 9-membered cyclic ethers for whose
synthesis the gauche effect can be exploited: (a) Crimmins, M. T.;
Powell, M. T. J. Am. Chem. Soc. 2003, 125, 7592-7595. (b) Crimmins,
M. T.; Emmitte, K. A.; Choy, A. L. Tetrahedron 2002, 58, 1817-1834.
(c) Baba, Y.; Saha, G.; Nakao, S.; Iwata, C.; Tanaka, T.; Ibuka, T.;
Ohishi, H.; Takemoto, Y. J. Org. Chem. 2001, 66, 81-88. (d) Crimmins,
M. T.; Choy, A. L. J. Org. Chem. 1997, 62, 7548-7549.
(41) Representative reviews about the RCM: (a) Deiters, A.; Martin,
S. F. Chem. Rev. 2004, 104, 2199-2238. (b) Schrock, R. R.; Hoveyda,
A. H. Angew. Chem. 2003, 115, 4740-4782; Angew. Chem., Int. Ed.
2003, 42, 4592-4633. (c) Fu¨rstner, A. Angew. Chem. 2000, 112, 3140-
3172; Angew. Chem., Int. Ed. 2000, 39, 3012-3043. (d) Maier, M. E.
Angew. Chem. 2000, 112, 2153-2157; Angew. Chem., Int. Ed. 2000,
39, 2073-2077. (e) Blechert, S. Pure Appl. Chem. 1999, 71, 1393-
1399. (f) Fu¨rstner, A. Top. Organomet. Chem. 1998, 1, 37-72. (g)
Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450. (h)
Schuster, M.; Blechert, S. Angew. Chem. 1997, 109, 2124-2145; Angew.
Chem., Int. Ed. Engl. 1997, 36, 2036-2055. (i) Schmalz, H.-G. Angew.
Chem. 1995, 107, 1981-1984; Angew. Chem., Int. Ed. Engl. 1995, 34,
1833-1836. (j) Felpin, F.-X.; Lebreton, J. Eur. J. Org. Chem. 2003,
3693-3712.
10544 J. Org. Chem., Vol. 70, No. 25, 2005

1-epi-Aglycon of the Cripowellins A and B
SCHEME 13. Intermolecular Coupling of 63 and
64 According to Kuwajima and Urabe
SCHEME 14. Retrosynthesis IV with a RCM and
an Intramolecular Heck Reaction as Key Steps
energy necessary for the Heck reaction. In fact, by
changing the reaction solvent to DMF to allow higher
reaction temperatures, the formation of the bicyclic
compound 76 was observed (Scheme 17).
regard to the existing problem of regioselectivity, and
asymmetric induction was virtually complete (ee g 98%).
Acetonide formation and saponification of the ester
functionality afforded the primary alcohol 75 in nearly
quantitative yield.
This alcohol was oxidized to the corresponding acid 71
over two steps, which was then used in the amide
coupling reaction without further purification. The other
coupling partner, amine 70, was synthesized by reductive
amination of bromopiperonal (60) with 3-buten-1-amine
(Scheme 16).
The amide 69 was obtained upon coupling with FEP
in a high yield of 66% over three steps. The RCM reaction
was first carried out with Grubbs’s first-generation
catalyst, yielding a mixture of the desired lactam 68 and
oligomers. In this reaction, Grubbs’s second-generation
catalyst led to a significant improvement as no oligomers
were detected by TLC analysis, and the lactam 68 was
isolated in 77% yield.
4.1. Heck Reactions. With the precursor for the
intramolecular Heck reaction in hand, we explored condi-
tions which had been described mainly by Overman et
al. in the general synthesis of bicyclic structures.48 Under
these conditions, only starting material could be isolated.
As the insertion of Pd0 into the aryl-bromine bond was
to be expected under these conditions (cf. to Scheme 13),
the reason for the failure may have been a high activation
Surprisingly, the bicyclic compound that is epimeric
at C1 in comparison to the natural products (see the
observed NOE) was exclusively obtained. Other phos-
phine ligands were also tested under these reaction
conditions (dppe, dppp, P(o-tol)3, P(2-furyl)3, PMePh2), but
all of them gave the same stereochemical outcome.
The following investigations revealed that it was very
hard to selectively functionalize the bicyclic compound
76. Neither hydroborations (BH3‚THF, THF; 9-BBN,
THF, reflux;49 CB, N,N-dimethylacetamide, DCM;50 CB,
SmI3, THF51), oxymercurations (Hg(OAc)2, THF/H2O;52
Hg(OAc)2, THF/H2O,)));53 Hg(OAc)2, THF/H2O, PTSA),
bromohydrin formation (NBS, DMSO/H2O),54 oxidation
with molecular oxygen (Co(tfa)2, O2, i-PrOH, MS 4 Å,
reflux),55 Wacker oxidations (PdCl2, CuCl, O2, DMF/H2O,
60-70 °C;56 PdCl2, EtOH, reflux57), oxidation with chromyl
chloride (CrO2Cl2, acetone, -78 °C f rt),58 nor oxidations
using AgI salts (Ag2CrO4, I2, pyr, DCM, 0 °C f rt;59
AgNO2, I2, Et2O60) proved successful in any way.
(49) Brown, H. C.; Knights, E. F.; Scouten, C. G. J. Am. Chem. Soc.
1974, 96, 7765-7770.
(50) Garrett, C. E.; Fu, G. C. J. Org. Chem. 1996, 61, 3224-3225.
(51) Evans, D. A.; Muci, A. R.; Stu¨rmer, R. J. Org. Chem. 1993, 58,
5307-5309.
(52) Brown, H. C.; Geoghegan, P. J., Jr. J. Org. Chem. 1970, 35,
1844-1850.
(53) Einhorn, J.; Einhorn, C.; Luche, J. L. J. Org. Chem. 1989, 54,
4479-4481.
(54) Guss, C. O.; Rosenthal, R. J. Am. Chem. Soc. 1955, 77, 2549-
2549.
(44) For secondary and tertiary amides in ring closing metatheses,
see: (a) Brouwer, A. J.; Liskamp, R. M. J. J. Org. Chem. 2004, 69,
3662-3668. (b) Banfi, L.; Basso, A.; Guanti, G.; Riva, R. Tetrahedron
Lett. 2003, 44, 7655-7658.
(55) Kato, K.; Yamada, T.; Takai, T.; Inoki, S.; Isayama, S. Bull.
Chem. Soc. Jpn. 1990, 63, 179-186.
(56) (a) Tsuji, J.; Nagashima, H.; Hori, K. Tetrahedron Lett. 1982,
23, 2679-2682. (b) Kang, S.-K.; Jung, K.-Y.; Chung, J.-U.; Namkoong,
E.-Y.; Kim, T.-H. J. Org. Chem. 1995, 60, 4678-4679.
(57) Lloyd, W. G.; Luberoff, B. J. J. Org. Chem. 1969, 34, 3949-
3952.
(45) Rao, J. A.; Cava, M. P. J. Org. Chem. 1989, 54, 2751-2753.
(46) The asymmetric dihydroxylation of allylic alcohols normally
proceeds with only moderate enantioselectivitysin contrast to their
corresponding p-methoxybenzoic acid esters: Corey, E. J.; Guzman-
Perez, A.; Noe, M. C. J. Am. Chem. Soc. 1995, 117, 10805-10816.
(47) Review: Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483-2547.
(58) (a) Freeman, F.; Cameron, P. J.; DuBois, R. H. J. Org. Chem.
1968, 33, 3970-3972. (b) Sharpless, K. B.; Teranishi, A. Y. J. Org.
Chem. 1973, 38, 8, 185-186.
(59) Hassner, A.; Kropp, J. E.; Kent, G. J. J. Org. Chem. 1969, 34,
2628-2632.
(48) Abelman, M. M.; Oh, T.; Overman, L. E. J. Org. Chem. 1987,
52, 4130-4133.
J. Org. Chem, Vol. 70, No. 25, 2005 10545

Enders et al.
SCHEME 15. Synthesis of the Acid 71
SCHEME 16. Synthesis of the 9-Membered Ring
Lactam 68
SCHEME 17. Successful Heck Reaction under
Neutral Conditions
78, which can also be considered to be an anti-Bredt
alkene, was really astonishing because the additional
ring strain in this bicyclic compound could not be
compensated by stability from the conjugation with the
aromatic moiety. The double bond of this bridgehead
alkene was not configurationally stable under the reac-
tion conditions employed since the E/Z-ratio was observed
to be time dependent (after 4 h (complete conversion):
E/Z ) 1:1.7, after 24 h E/Z ) 1:1, according to GC). Both
isomers could be separated by preparative HPLC, and
the major isomer was shown to possess the Z-configura-
tion (see the observed NOEs). Once again, the Heck
reaction was completely diastereoselective, and only the
isomer with the opposite orientation of the ethylene
bridge, when compared to the natural products, was
formed. To the best of our knowledge, this represents the
first successful example of a (highly diastereoselective)
intramolecular Heck reaction at a highly functionalized
(aza)cyclononene derivative.
Epoxidation of the olefin 76 was feasible. Nevertheless,
the reaction had to be carefully optimized. Dimethyldiox-
irane (DMDO) gave the best results because it permitted
the use of an excess of the reagent at lower temperature
(Scheme 18), avoiding decomposition which predominated
at higher temperatures. The epoxide 77 could be obtained
in a moderate yield of 55% after 9 days. The low yield
along with the long reaction time did not make this
approach very attractive.
Fortunately, screening other reaction conditions for the
Heck reaction was continued. Under conditions that are
generally regarded as cationic, the outcome of the Heck
reaction was completely changed (Scheme 19).
With 78 in hand, the synthesis of the 1-epi-aglycon was
within reach because a regiochemical differentiation
between olefinic carbons was assumed to be easier than
in the case of 76.
Our first attempt toward this goal is illustrated in
Scheme 20. After hydroboration with an excess of borane
(5 equiv) and quenching with water, the mixture of
The trisubstituted olefin 78 was isolated in 59% yield
as a mixture of E- and Z-isomers. Along with 78, minor
amounts of 76 were also formed (78/76 ) 8.2:1, according
to GC), which could be separated easily due to the higher
polarity of 76. The formation of this bridgehead alkene
(60) Cardillo, G.; Shimizu, M. J. Org. Chem. 1977, 42, 4268-4270.
10546 J. Org. Chem., Vol. 70, No. 25, 2005

1-epi-Aglycon of the Cripowellins A and B
SCHEME 18. Synthesis of the Epoxide 77
SCHEME 20. “Unexpected” Formation of the
Amine 79
tion. With an excess of SmI2 in the presence of t-BuOH,
the deoxygenation of 80 proceeded smoothly to give 81.61
The high yield of 99% in this reaction was astonishing
because R-hydroxy ketones are normally not regarded as
good reduction substrates for SmI2.62 Likewise, the
stability of the acetonide is noteworthy since the reduc-
tive cleavage of the R-C-O bond is commonly observed
(in the case of carboxylic acid esters).63
The final cleavage of the acetonide protecting group
to give the 1-epi-aglycon 82 of the cripowellins A and B
was most easily conducted in the presence of the acidic
ion-exchange resin Dowex-5064 because it made further
purification of the 1-epi-aglycon 82 unnecessarysin
contrast to the cleavage using PdCl2(CH3CN)2 in reflux-
ing CH3CN/H2O (1:1).65
SCHEME 19. Successful Heck Reaction under
Cationic Conditions
With regard to the known structure of the bisacetate
of cripowellin A and the biological activity of the cripo-
wellins, we were interested in the conformation of 82. In
the search for derivatives of the 1-epi-aglycon 82, our
efforts were rewarded by bisacetate 83, which provided
crystals suitable for an X-ray structure analysis.66
A
comparison of its crystal structure with the one obtained
from the bisacetate of cripowellin A clearly shows the
same spatial orientation of the keto and the lactam
carbonyl groups. Both are syn to each other and in the
same spatial proximity. This substructure had been
identified as the probable pharmacophor by researchers
of Bayer AG after extensive investigations on structure-
activity relationships.5 Therefore, it seems reasonable to
expect the 1-epi-aglycon 82 to be biologically active, too.
Yet, this still needs to be proven by biological tests.
Apart from confirming the relative stereochemistry of
83 and its predecessors, the X-ray structure also clarified
the fact that both the 1-epi-aglycon 82 and its bisacetate
83 seemed to have undetected carbonyl carbon signals
according to 13C NMR spectroscopy. The matter became
isomeric boronic acids was first oxidized to the corre-
sponding secondary alcohols and then further to the
ketone with the Dess-Martin periodinane (DMP).
The spectroscopic data of the isolated compound 79
clearly revealed that the amide group in 78 had under-
gone an undesired reduction to the corresponding amine.
The chemoselectivity problem could not be overcome by
performing the same reaction sequence with an equimo-
lar amount of borane.
4.2. Completion of the Synthesis of the 1-epi-
Aglycon. An alternative sequence proved to be more
successful (Scheme 21). The mixture of olefins 78 was
initially transformed into the R-hydroxy ketone 80 via a
two-step sequence of dihydroxylation and Swern oxida-
(61) White, J. D.; Somers, T. C. J. Am. Chem. Soc. 1994, 116, 9912-
9920.
(62) Molander, G. A.; Hahn, G. J. Org. Chem. 1986, 51, 1135-1138.
(63) Molander, G. A. Org. React. 1994, 46, 211-367.
(64) Ho, P.-T. Tetrahedron Lett. 1978, 19, 1623-1626.
(65) (a) Lipshutz, B. H.; Pollart, D.; Monforte, J.; Kotsuki, H.
Tetrahedron Lett. 1985, 26, 705-708. (b) Schmeck, C.; Hegedus, L. S.
J. Am. Chem. Soc. 1994, 116, 9927-9934.
(66) CCDC 263133 (83) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
J. Org. Chem, Vol. 70, No. 25, 2005 10547

Enders et al.
SCHEME 21. Completion of the Synthesis of the 1-epi-Aglycon 82 of the Cripowellins A and B
5-(6-Bromobenzo[1,3]dioxol-5-ylmethyl)-2,2-dimethyl-
3a,5,6,7,10,10a-hexahydro-1,3-dioxa-5-azacyclopentacy-
clononen-4-one (68). A flask containing a solution of the
bisolefin 69 (0.868 g, 1.9 mmol) in DCM (1.9 L) was evacuated
and filled with argon (4×). It was heated to reflux, and a
solution of Grubbs’ second-generation catalyst (0.163 g, 0.2
mmol) in DCM (10 mL) was added portionwise (2.5 mL each
30 min). After the last addition, reflux was continued for 1 h.
The solution was allowed to reach rt, and DMSO (0.68 mL,
9.6 mmol) was added. After stirring overnight and removal of
the solvent under reduced pressure, the residue was purified
by column chromatography (pentane/ether 1:1) to give 0.629
g (1.5 mmol, 77%) of the olefin 68 as a colorless foam. HPLC:
tR 12.3 min (LiChrosorb Si 60 (pentane/ether 4:6, 0.5 mL/min));
Rf 0.24 (pentane/ether 1:1); [R]25D +48.3 (c 0.4, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 1.48 (s, 3H), 1.58 (s, 3H), 2.32-2.44 (m,
1H), 2.50-2.66 (m, 3H), 3.33 (m, 1H), 3.70 (m, 1H), 4.03 (m,
1H), 4.08 (d, J ) 14.8, 1H), 4.50 (d, J ) 8.4, 1H), 5.05 (d, J )
14.8, 1H), 5.56 (m, 1H), 5.79 (m, 1H), 5.95 (s, 2H), 6.92 (s, 1H),
6.96 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 26.2, 26.3, 27.2, 28.5,
44.5, 50.4, 76.8, 79.9, 101.9, 110.1, 110.2, 112.3, 114.2, 128.1,
128.3, 129.2, 147.9, 170.4; MS (CI, 100 eV) m/z 345 (17), 344
(100), 215 (15), 213 (17); IR (CHCl3) 2990, 2938, 1657, 1480,
1377, 1238, 1167, 1091, 1039, 931, 886, 849, 802, 755, 665,
515. Anal. Calcd for C19H22BrNO5: C, 53.79; H, 5.23; N, 3.30.
Found: C, 53.53; H, 5.14; N, 2.99.
(4S,5R)-5-Allyl-2,2-dimethyl[1,3]dioxolane-4-carbox-
ylic Acid (6-Bromobenzo[1,3]dioxol-5-ylmethyl)but-3-
enylamide (69). A solution of DMSO (3.51 mL, 49.4 mmol)
in DCM (15 mL) was slowly added to a solution of oxalyl
chloride (2.03 mL, 23.7 mmol) in DCM (100 mL) at -78 °C.
After 15 min, a solution of the alcohol 75 (3.701 g, 21.5 mmol)
in DCM (15 mL) was added dropwise. Stirring was continued
for 30 min, after which Et3N (15.1 mL, 107 mmol) was added
slowly. Ten minutes later, the cold bath was removed, and
stirring was continued at room temperature for 10 min. An
aqueous workup (H2O; DCM; MgSO4) yielded the correspond-
ing aldehyde, which was purified by column chromatography
(pentane/ether 2:1). It was directly used for the next step: it
was dissolved in a mixture of water (60 mL) and acetone (60
mL), and the solution was cooled to 0 °C. 2-Methyl-2-butene
(42.0 mL, 395 mmol), NaH2PO4‚2H2O (6.705 g, 43.0 mmol),
and NaClO2 (80%, 6.074 g, 53.7 mmol) were added successively
clear after performing a high-temperature NMR experi-
ment on the bisacetate 83 which revealed its carbonyl
carbon signal again. One has to conclude that the bicyclic
system of both 82 and 83 adopts at least two conforma-
tional minima. On the NMR time scale, the exchange
between these minima is rather slow at room tempera-
ture, which causes significant line broadening (also
visible in their 1H NMR spectra, see the Supporting
Information). By heating the sample, this interconversion
is faster, the line broadening is reduced, and the signal
of the carbonyl carbon is easier to observe.
Conclusions. In this paper, we have described at-
tempts to achieve the asymmetric total synthesis of the
aglycon 3 of the cripowellins A (1) and B (2). Our efforts
were finally rewarded by featuring a sequence of a highly
enantioselective Sharpless dihydroxylation, a ring-closing
metathesis and a highly diastereoselective intramolecular
Heck reaction. This strategy allowed the construction of
the unusual [5.3.2]-bicyclic structure of the aglycon for
the first timesin the form of its 1-epi-analogue. The
synthesis is efficient (13 steps in the longest linear
sequence, 15 steps altogether; 5.6% overall yield), and
diastereo- and enantioselectivity are virtually complete
(de, ee g 98%). The crystal structure of the bisacetate of
the 1-epi-aglycon, 83, reveals the same spatial orientation
of the ketone and the lactam carbonyl groups as in the
case of the cripowellins. Therefore, it is reasonable to
assume that the 1-epi derivatives may exhibit the same
biological activity as the cripowellins and their aglycon
themselves. The 1-epi-aglycon 82 might clarify the hith-
erto unknown mode of action of the cripowellins.
Experimental Section
This section comprises all compounds belonging to the AD-
RCM-Heck approach (Chapter 4). A general procedure for an
aqueous workup, which is summarized in the form (quenching
agent; solvent used for extraction; drying agent), can be found
in the Supporting Information.
10548 J. Org. Chem., Vol. 70, No. 25, 2005

1-epi-Aglycon of the Cripowellins A and B
(vigorous stirring!). The ice bath was removed, and the reaction
was stirred at room temperature for 30 min. It was extracted
with EtOAc several times. The organic extracts were combined,
dried over MgSO4, and concentrated. All volatiles were re-
moved under high vacuum to yield the crude acid 71 (3.027 g,
16.3 mmol), which was dissolved in DCM (60 mL). The solution
was cooled to 0 °C, and the amine 70 (5.108 g, 18.0 mmol)
and FEP (4.233 g, 19.9 mmol) were added. Eti-Pr2N (8.6 mL,
52.0 mmol) was added dropwise, and the reaction was allowed
to warm to room temperature overnight. The reaction mixture
was concentrated to a small volume, which was subjected to
column chromatography (pentane/ether 4:1) to yield 6.398 g
(14.1 mmol, 66% over three steps) of the amide 69 as a colorless
oil. Rf 0.30 (pentane/ether 4:1); [R]25D +18.0 (c 0.7, CHCl3). The
NMR spectra clearly show the presence of two rotamers (ratio
about 1:1). For the interpretation of their 1H NMR spectra they
are treated as two different compounds: 1H NMR (400 MHz,
CDCl3) δ 1.39 (s, 6H), 1.43 (s, 3H), 1.46 (s, 3H), 2.28-2.51 (m,
8H), 3.22 (m, 1H), 3.33 (m, 1H), 3.40-3.61 (m, 2H), 4.13 (d, J
) 7.4, 1H), 4.27 (d, J ) 7.4, 1H), 4.51 (d, J ) 4.1, 1H), 4.55 (d,
J ) 2.2, 1H), 4.68-4.80 (m, 4H), 5.00-5.19 (m, 8H), 5.70-
5.93 (m, 4H), 5.95 (m, 2H), 5.98 (m, 2H), 6.66 (s, 1H), 6.70 (s,
1H), 6.98 (s, 1H), 7.02 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
26.1, 27.0, 31.6, 33.2, 37.1, 45.4, 46.3, 48.0, 50.6, 76.8, 76.9,
77.0, 101.6, 101.8, 107.9, 108.5, 110.0, 112.4, 112.7, 113.0,
113.6, 116.8, 117.5, 117.6, 129.0, 129.3, 133.35, 133.44, 134.1,
849, 771, 697, 614, 512. Anal. Calcd for C14H16O3: C, 72.39;
H, 6.94. Found: C, 72.13; H, 6.87.
(2R,3R)-4-Methoxybenzoic Acid 2,3-Dihydroxyhex-5-
enyl Ester (74). The olefin 73 (6.965 g, 30.0 mmol), MeSO2-
NH2 (2.854 g, 30.0 mmol), K2OsO4‚2H2O (66.3 mg, 0.18 mmol,
0.6 mol %), and AD-mix â (42 g, 1.4 g/mmol olefin) were added
successively to a mixture of water (150 mL) and t-BuOH (150
mL) at 0 °C. This suspension was stirred vigorously for 2.25
h, after which it was quenched by the addition of Na2SO3 (45
g, 1.5 g/mmol olefin). After the mixture was stirred for 5 min,
an aqueous workup (H2O; EtOAc; MgSO4) and column chro-
matography (pentane/EtOAc 1:2) gave 5.737 g (21.5 mmol,
72%) of the diol 74 as an amorphous solid. Note: The column
chromatography has to be conducted carefully in order to
separate the byproduct bearing the benzoyl group at one of
the secondary hydroxy groups (resulting from a migration of
the benzoyl protecting group under the basic conditions of the
Sharpless-AD). It is more polar than 74: Rf 0.80 (EtOAc); ee
g 98% (Chiralpak AD (n-heptane/i-PrOH 8:2, tR 14.5 min, 0.7
mL/min)); [R]23 +8.9 (c 1.9, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 2.31-2.48 (m, 3H), 2.75 (s, 1H), 3.73 (m, 1H), 3.86
(m, 1H), 3.87 (s, 3H), 4.38 (dd, J ) 11.6, 6.4, 1H), 4.47 (dd, J
) 11.6, 4.7, 1H), 5.13-5.22 (m, 2H), 5.87 (m, 1H), 6.93 (m,
2H), 8.00 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 38.1, 55.5, 66.2,
70.4, 71.8, 113.7, 118.5, 122.0, 131.8, 134.1, 163.7, 166.8; MS
(EI, 70 eV) m/z 266 (M+•, 2), 195 (11), 153 (28), 152 (25), 136
(10), 135 (100); IR (KBr) 3297, 2976, 2937, 2844, 1716, 1608,
1513, 1472, 1423, 1385, 1318, 1261, 1170, 1127, 1065, 1031,
995, 918, 848, 769, 696, 615, 542, 509. Anal. Calcd for
C14H18O5: C, 63.15; H, 6.81. Found: C, 62.93; H, 7.10.
134.8, 147.4, 147.6, 168.9, 169.0; MS (EI, 70 eV) m/z 453 (M+•
,
1), 451 (1), 373 (21), 372 (100), 215 (33), 213 (33), 141 (14), 83
(32), 55 (13); IR (CHCl3) 3077, 2985, 2934, 1652, 1480, 1374,
1239, 1163, 1111, 1040, 996, 925, 855, 803, 756, 672, 516. Anal.
Calcd for C21H26BrNO5: C, 55.76; H, 5.79; N, 3.10. Found: C,
55.79; H, 5.80; N, 3.35.
(2S,3S)-4-Methoxybenzoic Acid 2,3-Dihydroxyhex-5-
enyl Ester (ent-74). Analogous to the synthesis of 74, the
olefin 73 (0.232 g, 1.0 mmol) was reacted with AD-mix R to
give 0.176 g (0.66 mmol, 66%) of the diol ent-74 as an
amorphous solid (no additional K2OsO4‚2H2O was added in
this case, which accounts for the slightly lower yield): ee g
98% (Chiralpak AD (n-heptane/i-PrOH 8:2, Rt 16.3 min, 0.7
mL/min)); [R]23D -8.2 (c 0.8, CHCl3). The other analytical data
correspond to those of its enantiomer 74.
(6-Bromobenzo[1,3]dioxol-5-ylmethyl)but-3-enylam-
ine (70). Molecular sieves 4 Å (17 g) and 3-buten-1-amine
(3.690 g, 51.9 mmol) were added to a solution of bromopiper-
onal (60) (9.836 g, 43.0 mmol) in DCM (80 mL). After being
stirred overnight, the molecular sieves were removed by
filtration, and the solvent was evaporated under reduced
pressure. The crude imine was dissolved in methanol (130 mL)
and NaBH4 (1.626 g, 43.0 mmol) was added portionwise. After
the evolution of hydrogen had ceased, stirring was continued
for 1 h. All volatiles were evaporated under reduced pressure,
and the residue was subjected to an aqueous workup (H2O;
DCM; Na2SO4). Purification by column chromatography (pen-
tane/ether 3:1 f 2:1 f 1:1 f ether) gave 11.432 g (40.2 mmol,
94%) of the amine 70 as a colorless oil: Rf 0.24 (pentane/ether
(4R,5R)-(5-Allyl-2,2-dimethyl[1,3]dioxolan-4-yl)metha-
nol (75). PTSA (0.205 g, 1.1 mmol) was added to a solution of
the diol 74 (5.737 g, 21.5 mmol) in 2,2-DMP (150 mL). After 1
h, the reaction was worked up (satd NaHCO3 solution/H2O 1:1;
Et2O; MgSO4). The crude product was dissolved in methanol
(150 mL), and K2CO3 (4.466 g, 32.3 mmol) was added. Two
hours later, the reaction mixture was concentrated to a small
volume and subjected to an aqueous workup (H2O; DCM;
MgSO4). Purification by column chromatography (pentane/
ether 4:1 f 1:1) yielded 3.594 g of the alcohol 75 (20.9 mmol,
97% over two steps) as a colorless liquid: Rf 0.50 (pentane/
1
1:1); H NMR (300 MHz, CDCl3) δ 1.50 (s, 1H), 2.28 (m, 2H),
2.68 (t, J ) 6.8, 2H), 3.76 (s, 2H), 5.01-5.13 (m, 2H), 5.79 (m,
1H), 5.95 (s, 2H), 6.89 (s, 1H), 6.99 (s, 1H); 13C NMR (75 MHz,
CDCl3) δ 34.3, 48.0, 53.5, 101.6, 110.1, 112.7, 114.0, 116.4,
132.7, 136.4, 147.3, 147.4; MS (EI, 70 eV) m/z 285 (M+•, 2),
283 (2), 244 (35), 242 (36), 215 (100), 213 (94); IR (CHCl3) 3075,
2976, 2899, 2829, 1640, 1501, 1477, 1411, 1356, 1238, 1115,
1040, 995, 932, 866, 833, 780, 722, 657, 559. Anal. Calcd for
C12H14BrNO2: C, 50.72; H, 4.97; N, 4.93. Found: C, 50.29; H,
5.06; N, 5.25.
ether 1:1); [R]23 +25.2 (c 0.9, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 1.42 (s, 3H), 1,43 (s, 3H), 2.05 (t, J ) 5.9, 1H), 2.40
(m, 2H), 3.60 (m, 1H), 3.77-3.85 (m, 2H), 3.98 (dt, J ) 8.2,
6.0, 1H), 5.10-5.20 (m, 2H), 5.85 (m, 1H); 13C NMR (75 MHz,
CDCl3) δ 27.0, 27.3, 37.3, 61.9, 75.8, 81.0, 108.8, 117.9, 133.5;
MS (EI, 70 eV) m/z 157 (72), 141 (15), 131 (49), 83 (28), 79
(23), 69 (15), 67 (13), 59 (100), 55 (23), 54 (11); IR (film) 3432,
3079, 2986, 2932, 2878, 1643, 1455, 1435, 1376, 1246, 1168,
1062, 998, 917, 842, 694, 615, 515; HRMS calcd for C9H16O3 -
CH3 157.0865, found 157.0865.
(2E)-4-Methoxybenzoic Acid hexa-2,5-dienyl Ester (73).
Et3N (20 mL, 142 mmol) and a catalytic amount of DMAP were
added to a solution of (E)-2,5-hexadien-1-ol (4.549 g, 46.4
mmol) in DCM (120 mL) at 0 °C. A solution of p-methoxyben-
zoyl chloride (9.500 g, 55.7 mmol) in DCM (20 mL) was added,
and the reaction was allowed to warm to room temperature
overnight. An aqueous workup (1 M HCl; DCM; MgSO4) and
column chromatography (pentane/ether 10:1) gave 9.389 g
(40.4 mmol, 87%) of the ester 73 as a clear oil: Rf 0.58
(pentane/ether 4:1); 1H NMR (300 MHz, CDCl3) δ 2.84 (m, 2H),
3.85 (s, 3H), 4.76 (m, 2H), 5.01-5.11 (m, 2H), 5.66-5.92 (m,
3H), 6.91 (m, 2H), 8.00 (m, 2H); 13C NMR (75 MHz, CDCl3) δ
36.3, 55.4, 65.1, 113.6, 115.9, 122.8, 125.3, 131.6, 133.3, 135.9,
163.3, 166.1; MS (EI, 70 eV) m/z 232 (M+•, 7), 135 (100), 80
(28), 79 (16); IR (film) 3077, 3006, 2938, 2840, 1713, 1607, 1511,
1460, 1422, 1378, 1316, 1260, 1169, 1104, 1031, 976, 944, 919,
(1S,14S,16Z,18R)-16,16-Dimethyl-5,7,15,17-tetraoxa-12-
azapentacyclo[10.8.2.02,10.04,8.014,18]docosa-2,4(8),9,19-tet-
raen-13-one (76). A Schlenk tube with a screw cap and Teflon
seal was charged with Pd(OAc)2 (0.064 g, 0.29 mmol) and PPh3
(0.223 g, 0.85 mmol). Et3N (0.70 mL, 5.0 mmol) and a solution
of the olefin 68 (0.600 g, 1.4 mmol) in DMF (17 mL) were added
in a counterflow of Ar. After the tube had been sealed, it was
evacuated and filled with Ar (3×). It was placed in an oil bath
at 110 °C. Shortly afterward, a deep red color appeared, and
stirring was continued for 6 h. The mixture was allowed to
cool to room temperature. It was worked up (H2O; Et2O;
MgSO4) yielding a crude product that is dried under high
J. Org. Chem, Vol. 70, No. 25, 2005 10549

Enders et al.
vacuum (to remove residual DMF). Column chromatography
(pentane/EtOAc 1:1 f 1/2) gave 0.286 g (0.83 mmol, 59%) of
the bicyclic olefin 76 as a beige-brown foam (performing the
reaction on a smaller scale yields an almost colorless prod-
) 10.4, 8.0, 1H), 5.94 (m, 2H), 6.61 (s, 1H), 6.76 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 26.1, 27.1, 27.4, 34.5, 51.8, 52.1,
73.2, 84.5, 101.1, 109.3, 110.8, 126.1, 130.6, 131.0, 141.4, 146.1,
146.7, 173.1; MS (EI, 70 eV) m/z 344 (M+•, 24), 343 (100), 285
(11), 257 (38), 256 (11), 229 (15), 228 (25), 214 (13), 201 (12),
200 (29), 199 (12), 187 (27), 174 (12), 173 (18), 172 (11), 128
(11); IR (CHCl3) 2990, 2941, 1725, 1649, 1503, 1483, 1453,
1416, 1377, 1316, 1240, 1184, 1158, 1103, 1078, 1035, 936, 862,
822, 757, 670, 573, 522; HRMS calcd for C19H21NO5 343.1420,
found 343.1419.
Minor diastereomer (E-78): 1H NMR (400 MHz, CDCl3) δ
1.49 (s, 3H), 1.56 (s, 3H), 2.53-2.70 (m, 3H), 3.11 (ddd, J )
12.8, 10.6, 7.6, 1H), 3.47 (m, 1H), 3.94 (d, J ) 16.5, 1H), 3.94-
4.04 (m, 2H), 4.35 (d, J ) 8.2, 1H), 5.46 (dd, J ) 9.9, 6.3, 1H),
5.79 (d, J ) 16.8, 1H), 5.92 (m, 2H), 6.45 (s, 1H), 6.52 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 26.2, 27.3, 29.1, 32.6, 43.7, 52.6,
76.4, 80.1, 100.9, 106.4, 107.6, 110.2, 125.6, 134.3, 139.5, 145.9,
146.9, 171.1.
1
uct): Rf 0.29 (pentane/EtOAc 1:2); de g 98% (GC, H NMR);
[R]25D -55.3 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.33
(s, 3H), 1.44 (s, 3H), 1.88 (dt, J ) 15.4, 4.5, 1H), 2.66 (m, 1H),
3.46 (dd, J ) 13.7, 5.5, 1H), 3.75 (dd, J ) 8.4, 4.0, 1H), 3.95
(dt, J ) 4.8, 13.1, 1H), 4.02 (m, 1H), 4.14 (d, J ) 15.1, 1H),
4.80 (d, J ) 8.5, 1H), 4.99 (d, J ) 15.1, 1H), 5.90 (m, 4H), 6.60
(s, 1H), 6.70 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 25.6, 27.1,
29.6, 43.6, 44.0, 47.7, 76.5, 77.0, 101.0, 110.4, 111.2, 111.6,
130.5, 131.5, 132.5, 133.1, 145.3, 146.6, 169.8; MS (EI, 70 eV)
m/z 344 (M+•, 24), 343 (100), 286 (16), 285 (22), 257 (11), 256
(29), 229 (18), 228 (39), 215 (24), 199 (12), 187 (15), 185 (18),
174 (31), 173 (24), 172 (14), 161 (14), 135 (50), 115 (15); IR
(CHCl3) 3009, 2938, 2884, 1659, 1486, 1427, 1377, 1347, 1240,
1214, 1163, 1101, 1041, 998, 936, 870, 825, 756, 669, 476;
HRMS calcd for C19H21NO5 343.1420, found 343.1420.
(1R,14R,18R)-16,16-Dimethyl-5,7,15,17-tetraoxa-12-
azapentacyclo[10.8.2.02,10.04,8.014,18]docosa-2,4(8),9-trien-
20-one (79). BH3‚THF (1.5 mL of a 1 M solution in THF, 1.5
mmol) was added to a solution of the Heck product 78 (0.100
g, 0.29 mmol) in THF (2.5 mL). After 3 h, the reaction was
quenched by the addition of water (1 mL). NaBO3‚4H2O (0.090
g, 0.59 mmol) was added, and the resulting slurry was stirred
vigorously for 2 h. Workup (Et2O; MgSO4) and column chro-
matography (pentane/EtOAc 2:1) yielded a mixture of two
diastereomeric alcohols (0.054 g) which was dissolved in DCM
(2 mL). DMP (0.095 g, 0.22 mmol) was added, and after stirring
for 2.25 h, the reaction was quenched by the addition of
Na2S2O3 (1 g) and a saturated solution of NaHCO3 (10 mL).
The resulting mixture was stirred vigorously for 15 min and
worked up (DCM; MgSO4). Purification by column chroma-
tography (pentane/ether 1:2) gave the amine 79 as a colorless
foam: Rf 0.66 (pentane/EtOAc 1:2); de g 98% (1H NMR, GC);
[R]24D -99.7 (c 0.7, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.42
(s, 3H), 1.45 (s, 3H), 1.95-2.02 (m, 1H), 2.38 (t, J ) 11.5, 1H),
2.65 (dd, J ) 11.6, 3.0, 1H), 2.70-2.77 (m, 3H), 3.06 (t, J )
11.3, 1H), 3.14 (s, 1H), 3.17 (dd, J ) 12.1, 4.0, 1H), 3.66 (d, J
) 14.5, 1H), 3.75 (m, 1H), 3.79 (d, J ) 14.5, 1H), 4.04 (ddd, J
) 10.8, 8.7, 3.0, 1H), 5.89 (d, J ) 1.5, 1H), 5.93 (d, J ) 1.5,
1H), 6.50 (s, 1H), 6.55 (s, 1H); 13C NMR (75 MHz, CDCl3) δ
27.0, 27.1, 33.6, 39.8, 46.3, 55.8, 56.3, 62.0, 79.0, 80.7, 101.0,
107.9, 108.4, 110.8, 128.2, 130.8, 146.3, 146.5, 197.0; MS (EI,
70 eV) m/z 345 (M+•, 18), 330 (12), 300 (19), 287 (10), 242 (10),
203 (25), 202 (19), 196 (18), 175 (29), 174 (100), 161 (17), 131
(16), 103 (11); IR (CHCl3) 3012, 2946, 2871, 1668, 1504, 1487,
1460, 1364, 1326, 1277, 1233, 1164, 1132, 1073, 1041, 935, 899,
865, 842, 756, 668, 585, 563, 511, 460; HRMS calcd for C19H23-
NO5 345.1576, found 345.1576.
(1S,14S,18R)-1-Hydroxy-16,16-dimethyl-5,7,15,17-tet-
raoxa-12-azapentacyclo[10.8.2.02,10.04,8.014,18]docosa-2,4-
(8),9-triene-13,20-dione (80). K2OsO4‚2H2O (0.013 g, 0.04
mmol) and NMO (97%, 0.260 g, 2.2 mmol) were added to a
solution of the Heck product 78 (0.239 g, 0.70 mmol) in a
mixture of acetone (5 mL) and water (3.5 mL). After 3 h, the
reaction was quenched by the addition of Na2SO3 (0.200 g).
After stirring for 5 min, the reaction mixture was worked up
(DCM; MgSO4). The crude product could be used for the next
step without further purification.
DMSO (0.26 mL, 3.7 mmol) was added in one portion to a
solution of oxalyl chloride (0.15 mL, 1.8 mmol) in DCM (5 mL)
at -78 °C. After 15 min, a solution of the crude product (vide
supra) in DCM (4 mL) was added dropwise. Stirring was
continued for 30 min, after which Et3N (0.98 mL, 7.0 mmol)
was added slowly. Ten minutes later, the cold bath was
removed and stirring was continued until the reaction had
warmed to room temperature. Aqueous workup (H2O; DCM;
MgSO4) and column chromatography (ether) yielded 0.144 g
(0.38 mmol, 55% over two steps) of the R-hydroxy ketone 80
as a colorless solid: HPLC tR 10.1 min (LiChrosorb Si 60
(EtOAc/pentane 7:3), 7 mL/min); Rf 0.52 (EtOAc); de g 98%
(1R,14S,18R,19S,21S)-16,16-Dimethyl-5,7,15,17,20-pen-
taoxa-12-azahexacyclo[10.9.2.02,10.04,8.014,18.019,21]tricosa-
2,4(8),9-trien-13-one (77). The Heck product 76 (0.173 g, 0.50
mmol) was dissolved in a precooled (-24 °C) solution of DMDO
in acetone (13 mL of a 0.086 M solution, 1.1 mmol) and stored
in a freezer for 9 days at -24 °C. It was warmed to room
temperature and concentrated under reduced pressure. Puri-
fication by column chromatography (pentane/EtOAc 1:4) gave
0.100 g (0.28 mmol, 55%) of the epoxide 77 as a colorless
foam: Rf 0.23 (pentane/EtOAc 1:3); de 85% (GC, 13C NMR).
The following NMR data refer to the excess diastereomer: 1H
NMR (500 MHz, CDCl3) δ 1.35 (s, 3H), 1.47 (s, 3H), 2.14 (dt,
J ) 15.6, 4.4, 1H), 2.78 (m, 1H), 2.94 (dd, J ) 8.5, 7.6, 1H),
3.17 (dd, J ) 7.6, 4.3, 1H), 3.23 (t, J ) 4.7, 1H), 3.59 (dd, J )
14.0, 6.1, 1H), 3.98 (m, 2H), 4.11 (d, J ) 15.3, 1H), 4.98 (d, J
) 15.6, 1H), 5.02 (d, J ) 8.6, 1H), 5.91 (m, 2H), 6.67 (s, 1H),
6.74 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 25.7, 26.1, 27.3, 40.0,
44.6, 47.8, 57.9, 58.3, 73.6, 79.0, 101.2, 110.4, 113.3, 113.9,
127.5, 132.2, 145.8, 146.2, 169.6; MS (EI, 70 eV) m/z 360 (M+•
,
16), 359 (77), 344 (15), 302 (36), 301 (100), 244 (16), 227 (11),
215 (14), 199 (17), 176 (10), 175 (55), 174 (18), 173 (35), 172
(11), 161 (15), 131 (15), 115 (10), 103 (14); IR (CHCl3) 2992,
2937, 2889, 1661, 1486, 1427, 1378, 1336, 1290, 1249, 1214,
1156, 1104, 1060, 1037, 932, 888, 854, 832, 794, 755, 696, 667,
634, 603, 508, 480; HRMS calcd for C19H21NO6 359.1369, found
359.1369.
(14S,18R,20E/Z)-16,16-Dimethyl-5,7,15,17-tetraoxa-12-
azapentacyclo[10.8.2.02,10.04,8.014,18]docosa-1(20),2,4(8),9-
tetraen-13-one (78). A two-necked flask was charged with
the olefin 68 (0.560 g, 1.3 mmol), Pd(OAc)2 (0.045 g, 0.020
mmol), Ag2CO3 (1.092 g, 4.0 mmol), and dppp (0.109 g, 0.26
mmol). One neck was sealed with a septum, and the other one
was connected to a reflux condenser. A three-way stopcock
equipped with a ballon was used to seal the condenser. The
apparatus was evacuated and filled with Ar (3×). The ballon
was used to maintain a slight overpressure of Ar. Toluene (18
mL) was added through the septum, and the flask was placed
in an oil bath at 124 °C. After 4 h, the reaction was cooled to
room temperature and filtered through a short plug of silica
gel (eluting with EtOAc). The solvent was evaporated and the
residue purified by column chromatography (pentane/EtOAc
) 2:1 f 1:1 f 1:2) yielding 0.268 g (0.78 mmol, 59%) of the
bicyclic olefin 78 as a colorless foam: HPLC tR 19.9 min
(LiChrosorb Si 60 (Et2O/pentane 8:2), 0.6 mL/min; tR 15.7 min
for the minor diastereomer); Rf 0.50 (pentane/EtOAc 1:2); de
) 25% (referring to the double bond isomers); [R]24 -51.0 (c
D
0.3, CHCl3; Z-isomer).
Major diastereomer (Z-78): 1H NMR (400 MHz, CDCl3) δ
1.44 (s, 3H), 1.45 (s, 3H), 2.22 (ddd, J ) 14.4, 7.8, 4.5, 1H),
2.43 (ddd, J ) 12.8, 11.2, 6.8, 1H), 2.71 (dd, J ) 12.9, 7.1, 1H),
3.04 (dt, J ) 14.3, 10.0, 1H), 3.54 (dd, J ) 13.3, 6.7, 1H), 3.81
(m, 1H), 3.92 (d, J ) 15.9, 1H), 4.20 (ddd, J ) 9.5, 8.5, 4.5,
1H), 4.78 (d, J ) 8.2, 1H), 5.25 (d, J ) 15.7, 1H), 5.87 (dd, J
10550 J. Org. Chem., Vol. 70, No. 25, 2005

1-epi-Aglycon of the Cripowellins A and B
(1H NMR, HPLC); [R]22 -8.9 (c 0.4, CH3OH); melting point:
pressure to give 0.052 g (0.16 mmol, 56%) of the 1-epi-aglycon
of the cripowellins, 82, as a colorless solid: HPLC tR 3.7 min
(Kromasil 100 Sil (THF), 0.7 mL/min); Rf 0.40 (acetone); de g
D
1
>190 °C; H NMR (400 MHz, acetone-d6) δ 1.45 (s, 3H), 1.46
(s, 3H), 2.17 (dd, J ) 14.1, 7.8, 1H), 2.69 (dd, J ) 12.0, 4.8,
1H), 2.94 (s, 1H), 3.16-3.35 (m, 2H), 3.54 (t, J ) 11.7, 1H),
3.99-4.11 (m, 3H), 4.72-4.77 (m, 2H), 5.98 (d, J ) 1.1, 1H),
6.01 (d, J ) 1.1, 1H), 6.75 (s, 1H), 7.24 (s, 1H); 13C NMR (100
MHz, acetone-d6) δ 26.7, 27.5, 37.7, 41.3, 41.4, 53.7, 77.6, 80.3,
82.1, 102.0, 107.0, 108.5, 111.4, 128.0, 133.4, 147.3, 147.5,
169.8, 199.7; MS (EI, 70 eV) m/z 376 (M+•, 11), 375 (55), 347
(27), 289 (40), 288 (28), 272 (49), 263 (71), 260 (11), 243 (17),
242 (12), 233 (29), 232 (100), 204 (48), 190 (19), 189 (48), 188
(40), 177 (18), 176 (21), 175 (29), 163 (69), 136 (21), 135 (23),
85 (34), 59 (16); IR (KBr) 3286, 3061, 2987, 2929, 1711, 1654,
1487, 1452, 1376, 1327, 1231, 1178, 1101, 1039, 930, 884, 837,
785, 728, 650, 629, 568, 533; HRMS calcd for C19H21NO7
375.1318, found 375.1318.
(1R,14S,18R)-16,16-Dimethyl-5,7,15,17-tetraoxa-12-aza-
pentacyclo[10.8.2.02,10.04,8.014,18]docosa-2,4(8),9-triene-
13,20-dione (81). Preparation of a Solution of SmI2 in THF.
A solution of 1,2-diiodoethane (2.508 g, 8.9 mmol) in THF (9
mL) was added to a suspension of Sm powder (1.405 g, 9.3
mmol) in THF (9 mL). Shortly afterward, a vigorous evolution
of gas was observed. The mixture was stirred vigorously for 1
h, after which it was ready for use (the resulting deep blue
solution was assumed to be ca. 0.5 M).
98% (1H NMR); [R]23 +25.4 (c 0.4, CHCl3); mp >190 °C
D
(decomposition); 1H NMR (500 MHz, CHCl3) δ 2.44 (m 1H),
2.66 (dd, J ) 13.4, 4.9, 1H), 2.95 (m, 1H), 3.02 (m, 1H), 3.25
(s, 1H), 3.41 (m, 2H), 3.46 (t, J ) 3.8, 1H), 3.92 (m, 1H), 3.97
(d, J ) 16.8, 1H), 4.07 (m, 1H), 4.36 (t, J ) 9.0, 1H), 5.36 (dd,
J ) 16.6, 1.4, 1H), 5.93 (d, J ) 1.5, 1H), 5.97 (d, J ) 1.5, 1H),
6.48 (s, 1H), 6.67 (s, 1H); 13C NMR (125 MHz, CHCl3) δ 32.0,
40.7, 43.7, 51.5, 56.2, 72.3, 76.1, 101.4, 108.4, 111.7, 126.8,
128.9, 146.8, 147.4, 172.0; MS (EI, 70 eV) m/z 319 (M+•, 41),
274 (14), 246 (12), 190 (16), 175 (23), 174 (100), 173 (17), 162
(13), 161 (25), 149 (11), 131 (30), 103 (24), 77 (10); IR (CHCl3)
3392, 3017, 2899, 1696, 1644, 1504, 1488, 1447, 1357, 1218,
1042, 991, 937, 870, 759, 668, 524; HRMS calcd for C16H17-
NO6 319.1056, found 319.1056.
(1R,14S,15R)-14-(Acetyloxy)-13,17-dioxo-5,7-dioxa-12-aza-
tetracyclo[10.5.2.02,10.04,8]nonadeca-2,4(8),9-triene-15-
yl-acetate (83). Sc(OTf)3 (0.011 g, 0.02 mmol) was added to a
solution of the diol 82 (0.023 g, 0.07 mmol) in a mixture of
Ac2O (1 mL) and acetonitrile (1 mL). After being stirred for
2.5 h, the reaction was worked up (saturated solution of
NaHCO3; DCM; MgSO4). The crude product was dried under
high vacuum (to remove residual Ac2O). Purification by column
chromatography (ether/DCM 1:1) gave 0.019 g (0.05 mmol,
65%) of 83 as a colorless solid: HPLC tR 10.3 min (LiChrosorb
Si 60 (EtOAc/pentane 7:3), 0.7 mL/min); Rf 0.52 (ether/DCM
1:1); de g 98% (1H NMR); [R]23D -0.7 (c 0.2, CHCl3); mp >190
°C; 1H NMR (500 MHz, C5D5N) δ 2.02 (s, 3H), 2.11 (s, 3H),
2.35 (m, 1H), 2.93 (dd, J ) 13.1, 5.5, 1H), 3.14 (s, 1H), 3.41
(m, 2H), 3.69 (t, J ) 3.7, 1H), 3.98 (d, J ) 16.5, 1H), 4.51 (m,
1H), 5.57 (d, J ) 16.2, 1H), 5.81 (d, J ) 10.1, 1H), 5.93 (d, J )
1.1, 1H), 6.01 (d, J ) 1.1, 1H), 6.10 (s, 1H), 6.66 (s, 1H), 6.67
(s, 1H); 13C NMR (75 MHz, C5D5N) δ 20.0, 20.6, 32.8, 39.3,
43.1, 51.4, 56.6, 71.8, 71.9, 101.5, 108.5, 111.6, 128.1, 129.4,
t-BuOH (0.11 mL, 1.2 mmol) was added to a solution of the
R-hydroxy ketone 80 (0.144 g, 0.38 mmol) in THF (4 mL). The
freshly prepared SmI2 solution (ca. 5.5 mL, ca. 2.8 mmol, ca.
7.2 equiv) was then added dropwise until a green color of the
solution persisted for at least one minute. (Note: At the
beginning of the addition, the color changed from blue to yellow
almost instantaneously. The time needed for this color change
increased with the amount of SmI2 that was added to the
solution. Finally, a green color persisted for a couple of
minutes. Although this green color faded after some time as
well, the addition of SmI2 was stopped at this point.) The
reaction was stirred overnight, diluted with ether, and quenched
by the addition of water. The phases were separated, and the
aqueous phase was extracted several times with DCM (if both
phases did not separate, the precipitate could be dissolved by
adding a minimum amount of 1 N hydrochloric acid). The
organic extracts were combined, dried over K2CO3/MgSO4,
filtered, and concentrated. Purification by column chromatog-
raphy (ether) yielded 0.137 g (0.38 mmol, 99%) of the ketone
81 as a colorless solid: HPLC tR 10.7 min (LiChrosorb Si 60
1
146.7, 147.2, 167.4, 169.4, 170.5; H NMR (500 MHz, C5D5N,
70 °C) δ 1.99 (s, 3H), 2.07 (s, 3H), 2.32 (m, 1H), 2.84 (dd, J )
13.3, 5.3, 1H), 3.05 (m, 1H), 3.26 (dd, J ) 13.1, 9.8, 1H), 3.36
(ddd, J ) 15.3, 8.9, 6.4, 1H), 3.61 (t, J ) 3.8, 1H), 3.93 (d, J )
16.5, 1H), 4.40 (m, 1H), 5.50 (d, J ) 15.9, 1H), 5.73 (d, J )
10.1, 1H), 5.87 (d, J ) 1.2, 1H), 5.92 (m, 1H), 5.93 (d, J ) 1.2,
1H), 6.59 (s, 1H), 6.64 (s, 1H); 13C NMR (125 MHz, C5D5N, 70
°C) δ 19.9, 20.4, 32.8, 39.3, 43.3, 51.2, 56.7, 71.6, 72.3, 101.4,
108.5, 111.6, 128.3, 129.5, 146.8, 147.3, 167.1, 169.2, 170.3,
204.1; 1H NMR (500 MHz, CDCl3) δ 2.12 (2s, 6H), 2.44 (m,
1H), 2.66-2.78 (m, 2H), 2.96 (m, 1H), 3.43 (ddd, J ) 14.7, 8.4,
4.7, 1H), 3.53 (s, 1H), 3.96 (d, J ) 16.2, 1H), 4.16 (ddd, J )
15.0, 7.5, 7.5, 1H), 5.24 (d, J ) 16.2, 1H), 5.33 (s, 2H), 5.95 (d,
J ) 1.4, 1H), 5.98 (d, J ) 1.4, 1H), 6.47 (s, 1H), 6.72 (s, 1H);
MS (EI, 70 eV) m/z 403 (M+•, 21), 175 (14), 174 (100), 161 (14),
131 (11); IR (CHCl3) 3019, 2976, 2896, 2400, 1741, 1705, 1662,
1507, 1488, 1376, 1218, 1125, 1043, 935, 879, 780, 736, 670;
HRMS calcd for C20H21NO8 403.1267, found 403.1267.
(EtOAc/pentane 7:3), 0.7 mL/min); Rf 0.52 (EtOAc); de g 98%
1
(1H NMR, HPLC); [R]22 +11.9 (c 0.5, CHCl3); H NMR (400
D
MHz, CDCl3) δ 1.51 (s, 3H), 1.57 (s, 3H), 2.40 (m, 1H), 2.80
(dd, J ) 11.4, 4.8, 1H), 2.97 (m, 1H), 3.26 (t, J ) 11.4, 1H),
3.28 (m, 1H), 3.41 (dd, J ) 5.5, 1.9, 1H), 3.85 (dd, J ) 15.5,
9.2, 1H), 4.02 (d, J ) 16.5, 1H), 4.21 (ddd, J ) 11.4, 8.7, 4.9,
1H), 4.45 (d, J ) 8.8, 1H), 5.01 (d, J ) 16.8, 1H), 5.91 (d, J )
1.4, 1H), 5.96 (d, J ) 1.4, 1H), 6.48 (s, 1H), 6.65 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 26.3, 27.2, 32.7, 39.2, 42.4, 52.9,
57.2, 76.7, 80.7, 101.2, 108.4, 111.2, 111.4, 127.0, 127.5, 146.5,
147.1, 169.3, 203.7; MS (EI, 70 eV) m/z 359 (M+•, 3), 88 (11),
86 (66), 84 (100), 58 (62), 49 (12), 47 (16); IR (CHCl3) 2992,
2938, 2904, 1698, 1670, 1505, 1488, 1446, 1378, 1359, 1275,
1231, 1179, 1119, 1088, 1042, 991, 934, 904, 865, 821, 757,
667, 582, 543, 521; HRMS calcd for C19H21NO6 359.1369, found
359.1370.
Acknowledgment. This work was supported by the
Deutsche Forschungsgemeinschaft (SFB 380) and the
Fonds der Chemischen Industrie. We thank Prof. Rosen-
kranz, Prof. Stetter, and Dr. Lieb and co-workers of the
Bayer AG for valuable discussions at the beginning of
this project.
(1R,14S,15R)-14,15-Dihydroxy-5,7-dioxa-12-azatetra-
cyclo[10.5.2.02,10.04,8]nonadeca-2,4(8),9-triene-13,17-dione
(82). Dowex-50 (0.183 g) and water (14 mL) were added to the
ketone 81 (0.104 g, 0.29 mmol). This suspension was stirred
vigorously for 4.25 h. The solvent was removed by lyophiliza-
tion. The residue was taken up in CHCl3, and the solution was
filtered through a pad of glass wool (to remove the ion-
exchange resin). The solvent was removed under reduced
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 11, 13, 15-
17, 19-43, 45, 47-50, 53-59, and 62-65 and NMR spectra
of compounds 80-83. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO0518093
J. Org. Chem, Vol. 70, No. 25, 2005 10551