Enantioselective synthesis of (+)-isolysergol via ring-closing metathesis

Article abstract of DOI:10.1021/ol100819f

The first enantioselective synthesis of (+)-isolysergol was completed in 12 steps from commercially available materials by a novel approach that features a late stage microwave-mediated, diastereomeric ring-closing metathesis catalyzed by a chiral molybdenum catalyst to simultaneously form the D ring and set the stereocenter at C(8).

Full text of DOI:10.1021/ol100819f

ORGANIC
LETTERS
2010
Vol. 12, No. 11
2610-2613
Enantioselective Synthesis of
(+)-Isolysergol via Ring-Closing
Metathesis
Jason A. Deck and Stephen F. Martin*
Department of Chemistry and Biochemistry, The UniVersity of Texas, Austin, Texas
78712
sfmartin@mail.utexas.edu
Received April 9, 2010
ABSTRACT
The first enantioselective synthesis of (+)-isolysergol was completed in 12 steps from commercially available materials by a novel approach
that features a late stage microwave-mediated, diastereomeric ring-closing metathesis catalyzed by a chiral molybdenum catalyst to simultaneously
form the D ring and set the stereocenter at C(8).
The development of new and general strategies and tactics
for the efficient synthesis of biologically important natural
and unnatural substances is vital to advancing the science
of organic chemistry. In this context, we were attracted some
years ago to the potential of using ring-closing metathesis
(RCM)1,2 as a key construction for alkaloid synthesis,3 and
we have applied such reactions to the syntheses of a number
of alkaloids of varying complexity, including FR900482,
manzamine A, (+)-anatoxin-a, and dihydrocorynantheol as
well as other natural products.4
possibility of exploiting such a construction in the formula-
tion of a novel synthetic approach to the tetracyclic ergot
alkaloids. The ergot family of alkaloids has long attracted
the interests of synthetic chemists, because of the varied and
powerful biological activities of its members. Indeed, ergot
alkaloids and their derivatives are widely used in the clinic,
and there are numerous formulations containing natural or
semisynthetic ergot alkaloids for treating a diverse array of
human maladies.5 Moreover, the challenges associated with
preparing these alkaloids are legend, and despite numerous
successful syntheses of lysergic acid and its derivatives,6
there are only two reported enantioselective syntheses,6k,n
one of which relied upon a late stage resolution.6k There
are, however, no syntheses that exercise complete regio-
As part of an ongoing program to develop the utility and
scope of RCM reactions, we became intrigued by the
(1) For a general review of olefin metathesis and its applications, see:
Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, 2003;
Vols. 1-3
.
(2) For a general review of applications of RCM to the synthesis of
(4) For selected references, see: (a) Fellows, I. M.; Kaelin, D. E., Jr.;
Martin, S. F. J. Am. Chem. Soc. 2000, 122, 10781–10787. (b) Humphrey,
J. M.; Liao, Y.; Ali, A.; Rein, T.; Wong, Y.-L.; Chen, H.-J.; Courtney,
A. K.; Martin, S. F. J. Am. Chem. Soc. 2002, 124, 8584–8592. (c) Washburn,
D. G.; Heidebrecht, R. W., Jr.; Martin, S. F. Org. Lett. 2003, 5, 3523–
3525. (d) Brenneman, J. B.; Machauer, R.; Martin, S. F. Tetrahedron 2004,
60, 7301–7314. (e) Andrade, R. B.; Martin, S. F. Org. Lett. 2005, 7, 5733–
5735. (f) Deiters, A.; Pettersson, M.; Martin, S. F. J. Org. Chem. 2006, 71,
6547–6561. (g) Kummer, D. A.; Brenneman, J. B.; Martin, S. F. Tetrahedron
2006, 62, 11437–11449.
oxygen and nitrogen heterocycles, see: Deiters, A.; Martin, S. F. Chem.
ReV. 2004, 104, 2199–2238
.
(3) See for example: (a) Martin, S. F. In Handbook of Metathesis;
Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, 2003, Vol. 2, pp 338-352.
See also: (b) Martin, S. F.; Liao, Y.; Wong, Y.; Rein, T. Tetrahedron Lett.
1994, 35, 691–694. (c) Martin, S. F.; Liao, Y.; Chen, H.-J.; Pa¨tzel, M.;
Ramser, M. N. Tetrahedron Lett. 1994, 35, 6005–6008. (d) Martin, S. F.;
Chen, H.-J.; Courtney, A. K.; Liao, Y.; Pa¨tzel, M.; Ramser, M. N.; Wagman,
A. S. Tetrahedron 1996, 52, 7251–7264. (e) Neipp, C. E.; Martin, S. F. J.
Org. Chem. 2003, 68, 8867–8878. (f) Simila, S. T. M.; Martin, S. F. J.
Org. Chem. 2007, 72, 5342–5349.
(5) Mukherjee, J.; Menge, M. AdV. Biochem. Eng. Biotechnol. 2000,
68, 1–20.
10.1021/ol100819f  2010 American Chemical Society
Published on Web 05/12/2010

chemical control of the ∆9,10-double bond, the stereochem-
istry at C(8), and absolute stereochemistry. Thus, even though
50 years have passed since the first synthesis of lysergic acid,
unsolved problems remain, despite a myriad of advances in
synthetic methodology.
Toward designing an enantioselective route to the lysergate
group of alkaloids that addressed all of the stereo- and
regiochemical control issues, we developed the plan outlined
in Scheme 1. We envisioned that methyl lysergate (1) could
be accessed from the advanced intermediate 2 by oxidative
cleavage of the vinyl group at C(8) and deprotection of the
indole nitrogen atom. The ∆9,10-double bond in 2 would be
formed regioselectively via an asymmetric ring-closing
metathesis (ARCM) reaction of 3.7 This cyclization posed a
significant challenge to existing technology as it mandated
that the catalyst load selectively first onto one of the two
catalyst to optimize the diastereoselectivity could only be
addressed through experimentation. Indeed, the interesting
questions surrounding cyclizations of substrates like 3 via
ARCM processes provided a strong impetus for our efforts.
The preparation of 3 would then require the N-alkylation of
4, a reaction that was by no means certain. In earlier work
we had prepared racemic 4 from the dehydro tryptophan
derivative 5 by a sequence that featured a reductive Heck
cyclization.8 Accordingly, access to 4 in enantiomerically
pure form would require an enantioselective hydrogenation
of 5.
The known dehydroamino acid 5 was reduced with a S,S-
DIPAMP modified rhodium catalyst to give a protected
4-bromotryptophan derivative in nearly quantitative yield and
>90% enantioselectivity, thereby setting the absolute stere-
ochemistry at C(5) (Scheme 2).9 Processing of the methyl
ester into an acetylene moiety was achieved in a convenient,
one-pot procedure according to a process we had previously
developed that involved hydride reduction followed by
reaction of the intermediate aldehyde with Ohira’s reagent
to give 6 (80% ee).3e,10 Despite considerable experimentation,
Scheme 1. Approach to Methyl Lysergate (1)
Scheme 2. Assembly of the Carbon Framework
diastereotopic vinyl groups prior to the RCM with the
disubstituted exocyclic olefin. This process is to be contrasted
with the usual sequence of ARCM reactions that presumably
proceed by initial loading of the chiral catalyst onto the least
hindered double bond of a triene, followed by selective
cyclization involving one of the two enantiotopic olefins to
deliver the chiral product, often with high enantioselectivity.
Whether the desired cyclization of 3 would require a chiral
we were unable to avoid some racemization during this
process. Selective N-methylation of the carbamate moiety
proceeded smoothly to give 7. When N-methylation was
performed on the intermediate protected amino acid ester,
extensive racemization at C(5) was observed. Reductive
Heck cyclization of 7 in the presence of 1,2,2,6,6-
pentamethylpiperidine (PMP), followed by acid-catalyzed
removal of the Boc protecting group, gave 4 in 44% yield.
This sequence was conducted without purification of the
intermediate Heck product because the latter was con-
taminated with small quantities of the 7-membered ring
(6) For selected syntheses of and approaches to lysergic acid, see: (a)
Kornfield, E. C.; Fornefeld, E. J.; Kline, G. B.; Mann, M. J.; Morrison,
D. E.; Jones, R. G.; Woodward, R. B. J. Am. Chem. Soc. 1956, 78, 3087–
3114. (b) Oppolzer, W.; Francotte, E.; Båttig, K. HelV. Chim. Acta 1981,
64, 478–481. (c) Rebek, J., Jr.; Tai, D. F.; Shue, Y.-K. J. Am. Chem. Soc.
1984, 106, 1813–1819. (d) Ninomiya, I.; Hashimoto, C.; Kiguchi, T.; Naito,
T. J. Chem. Soc., Perkin Trans. 1 1985, 941–948. (e) Cacchi, S.; Ciattini,
P. G.; Morera, E.; Ortar, G. Tetrahedron Lett. 1988, 29, 3117–3120. (f)
Saa´, C.; Crotts, D. D.; Hsu, G.; Vollhardt, K. P. C. Synlett 1994, 487–489.
¨
(g) Ozlu¨, Y.; Cladingboel, D. E.; Parsons, P. J. Tetrahedron 1994, 50, 2183–
2206. (h) Barbey, S.; Mann, J. Synlett 1995, 27–28. (i) Marino, J. P., Jr.;
Osterhout, M. H.; Padwa, A. J. Org. Chem. 1995, 60, 2704–2713. (j)
Ralbovsky, J. L.; Scola, P. M.; Sugino, E.; Burgos-Garcia, C.; Weinreb,
S. M.; Parvez, M. Heterocycles 1996, 43, 1497–1512. (k) Moldvai, I.;
´
Temesva´ri-Major, E.; Incze, M.; Szentirmay, E.; Ga´cs-Baitz, E.; Sza´ntay,
C. J. Org. Chem. 2004, 69, 5993–6000. (l) Hendrickson, J. B.; Wang, J.
Org. Lett. 2004, 6, 3–5. (m) Inoue, T.; Yokoshima, S.; Fukuyama, T.
Heterocycles 2009, 79, 373–378. (n) Kurokawa, T.; Isomura, M.; Tokuyama,
H.; Fukuyama, T. Synlett 2009, 775–777.
(8) Lee, K. L.; Goh, J. B.; Martin, S. F. Tetrahedron Lett. 2001, 42,
1635–1638.
(9) Yokoyama, Y.; Matsumoto, T.; Murakami, Y. J. Org. Chem. 1995,
60, 1486–1487.
(7) For a review of ARCM, see: Schrock, R. R.; Hoveyda, A. H. Angew.
Chem., Int. Ed. 2003, 42, 4592–4633.
(10) Dickson, H. D.; Smith, S. C.; Hinkle, K. W. Tetrahedron Lett. 2004,
45, 5597–5599
.
Org. Lett., Vol. 12, No. 11, 2010
2611

product 8 together with other impurities that were difficult
to remove.
heating (50 W, 30 min) of 3 in the presence of 15 again
provided a mixture of 10 and 2, but with improved yields of
55% and 20%, respectively. The antipodal Schrock-Hoveyda
ent-15 catalyst did not grant favoritism of 2 versus 10 and
gave instead only trace amounts of 2 and 10, presumably as
a consequence of being mismatched. We also examined
several other chiral molybdenum-derived catalysts that had
been more recently developed by Hoveyda, but none of these
led to improved levels of diastereoselectivity for either 10
or 2.
At this juncture, it was necessary to convert 4 into the
triene 3. Preliminary attempts to introduce the branched
dienyl group onto 4 via alkylation with 3-bromo-1,4-
pentadiene or similar amidation followed by selective reduc-
tion were unsuccessful. We eventually discovered, via
extensive experimentation with reaction conditions and
various pentadienyl organometallic agents, that reaction of
the putative N,O-acetal derived from 4 with bispentadienylz-
inc provided 3 and 9 as an easily separable mixture (2:1) in
91% yield and 2:1 regioselectivity.11
Scheme 4
.
ARCM and Completion of the Synthesis of
(+)-Isolysergol (13)
Scheme 3. Setting up the ARCM
With triene 3 available, the key RCM was at hand.
However, reaction of 3 with Grubbs I and II catalysts as
well as Schrock’s catalyst (14) either at room temperature
or upon heating to 100 °C gave no isolable cyclization
product. Similarly, analogues of 3 wherein the N-Me group
had been exchanged for an N-Boc group or quaternized with
iodomethane would not undergo metathesis. While it is well-
known that microwave heating can accelerate and improve
the efficiency of transition metal mediated processes,12 we
are aware of no example of the use of microwave heating
with molybdenum based metathesis catalysts. We were
therefore delighted to find that heating 3 in the presence of
14 using microwave irradiation (300 W, 10 min) and forced
air cooling did indeed induce a diastereoselective RCM to
provide 10 and 2 in about 36% and 8% yields, respectively.
The relative configurations of 10 and 2 were deduced via
nOe correlations of protons on the D-ring and the pendant
vinyl group relative to the proton of known configuration at
C(5) as shown. Because substrate-based control in the RCM
led to the preferential formation of the undesired “iso”
product 10, we queried whether a chiral RCM catalyst might
override this inherent diastereoselection and deliver increased
amounts of 2. Although no substrates of the complexity of
3 have been subjected to ARCM reactions, a review of the
literature suggested that the Schrock-Hoveyda catalyst 1513
might generate 2 as the major product. However, microwave
Conversion of either 2 or 10 into methyl lysergate (1) or
methyl isolysergate via oxidative cleavage of the vinyl group
at C(8) proved to be an insurmountable challenge, a difficulty
we attributed to the apparent instability of the intermediate
aldehyde.14 After considerable experimentation, we discov-
ered that the vinyl group in 10 could be cleaved by selective
dihydroxylation of the terminal olefin, using a protocol
reported by Donohoe, to give diols 11 as an inconsequential
mixture (6.5:1) of diastereomers.15 Attempted oxidation of
an analogue of 11 having a protected primary alcohol to give
(11) For related additions, see: (a) Courtois, G.; Harama, M.; Miginiac,
P. J. Organomet. Chem. 1981, 218, 275–298. (b) Alvaro, G.; Grepioni, F.;
Grilli, S.; Maini, L.; Martelli, G.; Savoia, D. Synthesis 2000, 581–587.
(12) For some recent leading references, see: (a) Michaut, A.; Boddaert,
T.; Coquerel, Y.; Rodriguez, J. Synthesis 2007, 2867–2871. (b) Coquerel,
Y.; Rodriguez, J. Eur. J. Org. Chem. 2008, 1125–1132. (c) Nicks, F.;
Borguet, Y.; Delfosse, S.; Bicchielli, D.; Delaude, L.; Sauvage, X.;
Demonceau, A. Aust. J. Chem. 2009, 62, 184–207.
(14) Lysergaldehyde has not been characterized, and the few reports
dealing with it or derivatives thereof describe only difficulties in formation
of the aldehyde. For examples, see: (a) Lin, C.-C. L.; Blair, G. E.; Cassady,
J. M.; Gro¨ger, D.; Maier, W.; Floss, H. G. J. Org. Chem. 1973, 38, 2249–
2251. (b) Choong, T. C.; Thompson, B. L.; Shough, H. R. J. Pharm. Sci.
1977, 66, 1340–1341.
(13) Alexander, J. B.; La, D. S.; Cefalo, D. R.; Hoveyda, A. H.; Schrock,
R. R. J. Am. Chem. Soc. 1998, 120, 4041–4042.
(15) Donohoe, T. J.; Moore, P. R.; Waring, M. J. Tetrahedron Lett. 1997,
38, 5027–5030.
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Org. Lett., Vol. 12, No. 11, 2010

the corresponding ketone led to an intractable mixture, further
supporting the unstable nature of such compounds having
an aldehyde or a ketone at C(8) rather than the more
commonly observed carboxylic acid derivatives. Subsequent
reaction of 11 with periodic acid in the presence of TFA,
followed by immediate reduction of the unstable aldehyde
thus produced with NaBH3CN, then furnished 12 in 83%
yield. Removal of the tosyl protecting group from the indole
nitrogen atom delivered (+)-isolysergol (13). Synthetic 13
displayed spectral characteristics (1H NMR, 13C NMR, TLC,
HPLC) identical with those in the literature and with an
authentic sample of racemic 13 provided by Professor
Ohno.16 The ee of 13 thus obtained was determined to be
85% using chiral HPLC in comparison with racemic 13.
In summary, we have completed the first enantioselective
synthesis of isolysergol. The synthesis features a novel RCM,
which was promoted by the chiral catalyst 15 using
microwave heating, of the complex triene 3 bearing diaste-
reotopic vinyl groups to give preferentially 10, a cyclization
that is enhanced through the agency of the chiral catalyst
15. The synthesis requires a total of only 12 steps from
commercially available 4-bromoindole. Other applications
of olefin metathesis to solving problems in the total synthesis
of complex natural products are under active investigation,
and the results of these studies will be disclosed in due
course.
Acknowledgment. We thank the National Institutes of
Health (GM 25439), the Robert A. Welch Foundation, Pfizer,
Inc., Merck Research Laboratories, and Boehringer Ingelheim
Pharmaceuticals for their generous support of this research.
We are also grateful to Dr. Richard Pederson (Materia, Inc.)
for catalyst support, Professor Amir Hoveyda (Boston
College) for generous gifts of chiral Mo-derived catalysts,
and Professor Hiroaki Ohno (Graduate School of Pharma-
ceutical Sciences, Kyoto University) for providing a generous
sample of syntheic, racemic isolysergol. J.A.D. would like
to thank Dr. Kenner C. Rice (National Institute on Drug
Abuse, National Institutes of Health) for helpful discussions
and support during the final stages of the project.
Supporting Information Available: Experimental pro-
cedures, spectral data, and copies of 1H and 13C NMR spectra
for all synthetic intermediates and 13. This material is
available free of charge via the Internet at http://pubs.acs.org.
(16) (a) Ninomiya, I.; Hashimoto, C.; Kiguchi, T.; Naito, T.; Barton,
D. H. R.; Lusinchi, X.; Milliet, P. J. Chem. Soc., Perkin Trans. 1 1990,
707–713. (b) Inuki, S.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2008, 10,
5239–5242.
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