Catalytic asymmetric synthesis of the central tryptophan residue of celogentin C

Article abstract of DOI:10.1021/ol035236x

(Equation presented) Chiral phase-transfer catalyst 5 containing an electron-deficient trifluorobenzyl moiety promoted the alkylation of glycine derivative 6 with propargyl bromide 7a in good yield and excellent ee. The resulting propargyl glycine 8 was c

Full text of DOI:10.1021/ol035236x

ORGANIC
LETTERS
2003
Vol. 5, No. 20
3611-3614
Catalytic Asymmetric Synthesis of the
Central Tryptophan Residue of
Celogentin C
Steven L. Castle* and G. S. C. Srikanth
Department of Chemistry and Biochemistry, Brigham Young UniVersity,
ProVo, Utah 84602
scastle@chem.byu.edu
Received July 3, 2003
ABSTRACT
Chiral phase-transfer catalyst 5 containing an electron-deficient trifluorobenzyl moiety promoted the alkylation of glycine derivative 6 with
propargyl bromide 7a in good yield and excellent ee. The resulting propargyl glycine 8 was converted to 14, the central tryptophan residue
of Celogentin C, in two steps, with the Pd-catalyzed heteroannulation as the key transformation. This method promises to be an efficient route
for the preparation of tryptophan derivatives possessing substitution on the indole ring.
Celogentin C (1, Figure 1) is a bicyclic octapeptide isolated
from the seeds of Celosia argentea.1 It is the most potent
member of the moroidin family of natural products, a group
of structurally similar bicyclic peptides characterized by their
inhibition of the polymerization of tubulin.2 The unusual
architecture of 1 is derived from two cross-links, one joining
the leucine â-carbon with the indole C-6 of tryptophan, and
the other connecting the tryptophan indole C-2 with the
imidazole N-1 of histidine. Synthetic studies of moroidin
natural products are limited to the work of Moody resulting
in the preparation of the right-hand macrocycle of moroidin.3
Clearly, any synthesis of 1 will need to address the
preparation of a tryptophan derivative with functionality at
the indole C-2 and C-6 positions that is appropriate for
constructing the aforementioned strategic bonds. Herein, we
report our synthesis of such a molecule as well as our parallel
investigations in the area of phase-transfer-catalyzed asym-
metric alkylation.
Although several processes have been developed for the
synthesis of optically active tryptophan derivatives possessing
substituted indoles,4 we were attracted to the recent report
by Cook and co-workers.5 They have disclosed a versatile
synthesis of tryptophans (Scheme 1) in which the indole
(1) Kobayashi, J.; Suzuki, H.; Shimbo, K.; Takeya, K.; Morita, H. J.
Org. Chem. 2001, 66, 6626.
(2) (a) Leung, T.-W. C.; Williams, D. H.; Barna, J. C. J.; Foti, S.;
Oelrichs, P. B. Tetrahedron 1986, 42, 3333. (b) Kahn, S. D.; Booth, P. M.;
Waltho, J. P.; Williams, D. H. J. Org. Chem. 1989, 54, 1901. (c) Morita,
H.; Shimbo, K.; Shigemori, H.; Kobayashi, J. Bioorg. Med. Chem. Lett.
2000, 10, 469.
(3) (a) Harrison, J. R.; Moody, C. J. Tetrahedron Lett. 2003, 44, 5189.
(b) Comber, M. F.; Moody, C. J. Synthesis 1992, 731.
Figure 1. Celogentin C (1).
10.1021/ol035236x CCC: $25.00
© 2003 American Chemical Society
Published on Web 08/30/2003

Scheme 1. Cook Tryptophan Synthesis
moiety is formed via the palladium-catalyzed heteroannu-
lation chemistry of Larock.6 This process permits functional-
ity at C-6 of the indole product, and it results in the presence
of a triethylsilyl (TES) group at the indole C-2. Thus, the
Cook method would appear to be ideal for our purposes;
however, it suffers from its reliance on a stoichiometric
amount of the Scho¨llkopf chiral auxiliary.7 It occurred to us
that we could rectify this shortcoming of an otherwise useful
protocol by employing the chiral phase-transfer-catalyzed
alkylation of a glycinate Schiff base8 in place of the
diastereoselective alkylation of the Scho¨llkopf reagent.
Although selected examples exist of highly enantioselec-
tive phase-transfer-catalyzed alkylations of glycinate Schiff
bases with propargylic electrophiles,9 we were unsure of the
prospects for obtaining suitable enantioselectivity in our case.
In alkylations of the Scho¨llkopf reagent with TMS-propar-
gylic electrophiles, Cook observed dramatic variations in
diastereoselectivities (2.5:1 to 46:1) with respect to the
leaving group. The propargyl bromide provided the lowest
levels of selectivity, and the analogous diphenyl phosphate
delivered the best results.5 Additionally, Ley’s chiral glycine
equivalent affords high levels of diastereoselectivity (g10:
1) in alkylations with several electrophiles but gives signifi-
cantly reduced selectivity (3:1) with propargyl bromide.10
With these results in mind, we initiated a study of the
Figure 2. Phase-transfer catalysts surveyed.
enantioselective alkylation of glycinate Schiff base 611 with
TES-propargyl bromide (7a) using chiral phase-transfer
catalysts 2-5 (Figure 2, Table 1).
Table 1. Phase-Transfer-Catalyzed Alkylation of 6 with 7aa
catalyst
conditionsb
yield (%)
ee (%)c
2
3
4
5
A
B
C
D
65
54
80
80
79d
84
81
90
(4) (a) Wang, W.; Xiong, C.; Zhang, J.; Hruby, V. J. Tetrahedron 2002,
58, 3101. (b) Yokoyama, Y.; Osanai, K.; Mitsuhashi, M.; Kondo, K.;
Murakami, Y. Heterocycles 2001, 55, 653. (c) Drury, W. J., III; Ferraris,
D.; Cox, C.; Young, B.; Lectka, T. J. Am. Chem. Soc. 1998, 120, 11006.
(d) Zembower, D. E.; Ames, M. M. Synthesis 1994, 1433. (e) Lee, M.;
Phillips, R. S. Bioorg. Med. Chem. Lett. 1992, 2, 1563. (f) Sato, K.;
Kozikowski, A. P. Tetrahedron Lett. 1989, 30, 4073.
a Data are the average of two runs. b A: 0.01 equiv of 2, toluene-50%
aq KOH 3.25:1, 0 °C, 1 h. B: 0.1 equiv of 3, 10 equiv of CsOH‚H2O,
CH2Cl2, -78 °C, 22 h. C: 0.04 equiv of 4, (toluene/CHCl3 7:3)-50% aq
KOH 3:1, 0 °C, 3 h. D: 0.1 equiv 5, (toluene/CHCl3 7:3)-50% aq KOH
3:1, 0 °C, 2 h. 5 equiv of 7a was used in all cases. c Determined by HPLC
(Chiralcel OD-H, 99.8:0.2 hexanes:i-PrOH, 1 mL/min). d ent-8 was obtained.
(5) Ma, C.; Liu, X.; Li, X.; Flippen-Anderson, J.; Yu, S.; Cook, J. M. J.
Org. Chem. 2001, 66, 4525.
(6) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689.
(7) Scho¨llkopf, U.; Groth, U.; Deng, C. Angew. Chem., Int. Ed. Engl.
1981, 20, 798. The precursor to the antipode of the Scho¨llkopf reagent
necessary for the preparation of natural amino acids, (R)-(-)-3-isopropyl-
2,5-piperazinedione, is available from Aldrich at a cost of $34.80/g.
Alternatively, the reagent can be synthesized via a four-step procedure5
employing the pulmonary toxin phosgene.
In this survey of catalysts for the preparation of propargyl
glycine 8 from 6 and 7a, we employed the optimized reaction
conditions reported for each catalyst. Our suspicions were
confirmed, as BINOL-derived catalyst 29b and cinchonidine-
derived catalysts 39a and 49c all delivered 8 in moderate ee.
(8) O’Donnell, M. J. Aldrichim. Acta 2001, 34, 3.
(9) (a) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119,
12414. (b) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2003,
125, 5139. (c) Park, H.-g.; Jeong, B.-S.; Yoo, M.-S.; Lee, J.-H.; Park, M.-
k.; Lee, Y.-J.; Kim, M.-J.; Jew, S.-s. Angew. Chem., Int. Ed. 2002, 41,
3036. (d) Jew, S.-s.; Yoo, M.-S.; Jeong, B.-S.; Park, I.-Y.; Park, H.-g. Org.
Lett. 2002, 4, 4245. (e) Park, H.-g.; Jeong, B.-S.; Yoo, M.-S.; Lee, J.-H.;
Park, B.-s.; Kim, M. G.; Jew, S.-s. Tetrahedron Lett. 2003, 44, 3497.
(10) Dixon, D. J.; Harding, C. I.; Ley, S. V.; Tilbrook, D. M. G. Chem.
Commun. 2003, 468.
3612
Org. Lett., Vol. 5, No. 20, 2003

Additionally, modest yields due to competitive hydrolysis
of the imine moiety of 6 were observed in reactions with
catalysts 2 and 3. Fortunately, the electron-poor catalyst 5
recently disclosed by Park and Jew9d provided 8 in good
yield and ee.
Scheme 2. Synthesis of Heteroannulation Partners
With the selection of 5 as the optimal catalyst, we next
investigated the effect of the propargylic leaving group on
the enantioselectivity (Table 2).12 In contrast to Cook’s study
Table 2. Effect of Leaving Group on Alkylationa
electrophile
X
yield (%)
ee (%)
7a
7b
7c
7d
7e
7f
Br
I
Cl
OMs
OTs
80
71
13
35
90
92
85
81
NRb
NR
79
With ample quantities of 8 in hand, we next addressed
the preparation of the coupling partners for the heteroannu-
lation reaction (Scheme 2). Exchange of the rather labile
benzophenone imine moiety for the more robust Cbz
protecting group provided alkyne 9. Iodoaniline 13 was
synthesized from 4-iodo-3-nitrobenzoic acid (10)13 via a high-
yielding three-step sequence.
The palladium-catalyzed heteroannulation of alkyne 9 and
iodoaniline 13 to form tryptophan 14 is illustrated in Scheme
3. A variety of conditions were examined,6,14 and the best
OPO(OPh)2
Br
7ac
94
a Data are the average of two runs. b No reaction observed. c Reaction
performed at -20 °C.
with the Scho¨llkopf reagent, our investigations of the phase-
transfer-catalyzed alkylation of 6 revealed only a modest
variation in ee with respect to leaving group. Among the
propargyl halides, iodide 7b provided 8 with slightly better
ee but lower yield than did bromide 7a, presumably due to
the instability of 7b. Alkylations with chloride 7c were char-
acterized by poor yields and moderate ee values. Of the non-
halogen leaving groups examined, only mesylate 7d delivered
8, albeit in low yield and moderate ee. Fortunately, when
the alkylation of 6 with 7a was performed at -20 °C, 8 was
obtained in 94% ee with essentially no sacrifice in yield.
As we turned our attention to performing the alkylation
on a scale more suited to preparative work, we desired to
reduce the number of equivalents of 7a used in the reaction.
Unfortunately, this led to a significant decrease in the reaction
rate. We were hesitant to allow the reaction to proceed for
long periods of time due to the likelihood of increased levels
of imine hydrolysis of 6. We were pleased to find an
acceptable compromise by performing the reaction on a ca.
1 mmol scale with 2.5 equiv of 7a at -20 °C for 7 h. Using
these conditions, we isolated 8 in 66% yield (75% based on
recovered 6) along with 11% of 6 and 53% of 7a. Thus,
although excess 7a is required in the alkylation to ensure a
useful rate, the unreacted bromide can be almost completely
recovered from the reaction. Moreover, the ability to recover
the phase-transfer catalyst from the reaction mixture9a makes
this process quite economical and attractive for large-scale
synthesis.
Scheme 3. Synthesis of Tryptophan 14
results were obtained from a slight modification of Cook’s
protocol.5 In each case, varying amounts of unreacted 9 were
observed, whereas 13 was never recovered even in cases
where it was used in excess. This suggests that decomposition
of 13 may be responsible for the attenuated yield. Compari-
son of the chiral HPLC profile (Chiralcel OD-H) of 14 with
that of a racemic sample indicated that no racemization
occurred under the basic heteroannulation conditions.
In conclusion, we have discovered that the trifluorobenzyl
phase-transfer catalyst 5 is uniquely effective among the
catalysts studied for the alkylation of glycinate Schiff base
6 with propargyl bromide 7a. This catalyst may prove useful
in other demanding alkylations. Variation of the propargylic
leaving group resulted in relatively small changes in enan-
tioselectivity compared to the large changes in diastereose-
lectivity observed by Cook in alkylations of the Scho¨llkopf
(11) O’Donnell, M. J.; Polt, R. L. J. Org. Chem. 1982, 47, 2663.
(12) The electrophiles for this study were synthesized by the following
procedures. 7a: Jones, G. B.; Wright, J. M.; Plourde, G. W., II; Hynd, G.;
Huber, R. S.; Mathews, J. E. J. Am. Chem. Soc. 2000, 122, 1937. 7b: Rigby,
J. H.; Cuisiat, S. V. J. Org. Chem. 1993, 58, 6286. 7c: Marshall, J. A.;
Wallace, E. M.; Coan, P. S. J. Org. Chem. 1995, 60, 796. 7d: Magnus, P.;
Exon, C.; Albaugh-Robertson, P. Tetrahedron 1985, 41, 5861. 7e,f: ref 5.
(13) Collini, M. D.; Ellingboe, J. W. Tetrahedron Lett. 1997, 38, 7963.
(14) Gathergood, N.; Scammells, P. J. Org. Lett. 2003, 5, 921.
Org. Lett., Vol. 5, No. 20, 2003
3613

reagent. Finally, we were able to convert the alkylation
product 8 into the functionalized tryptophan derivative 14,
thereby demonstrating that phase-transfer-catalyzed asym-
metric alkylation can be used to increase the efficiency of
the Cook tryptophan synthesis by eliminating the need for a
stoichiometric chiral auxiliary. Studies involving the incor-
poration of 14 into a total synthesis of 1 are currently in
progress.
assistance in catalyst preparation. This Letter is dedicated
to Professors Dale L. Boger and Larry E. Overman on the
occasion of their 50th and 60th birthdays, respectively.
Supporting Information Available: Spectral data for
7a-f, and experimental procedures and spectral data for 8,
9, and 11-14. This material is available free of charge via
the Internet at http://pubs.acs.org.
Acknowledgment. We thank Brigham Young University
for support of this work and Sashikumar Mettath for
OL035236X
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Org. Lett., Vol. 5, No. 20, 2003