Asymmetric synthesis of (-)-martinellic acid

Article abstract of DOI:10.1021/ol4007508

A high-yielding total asymmetric synthesis of (-)-martinellic acid is reported. The conjugate addition of lithium (R)-N-allyl-N-(α-methyl-4- methoxybenzyl)amide to tert-butyl (E)-3-[2′-(N,N-diallylamino)-5′- bromophenyl]propenoate and alkylation of the resultant β-amino ester have been used as the key steps to install the C(9b) and C(3a) stereogenic centers, respectively, and a highly diastereoselective Wittig reaction/intramolecular Michael addition was then used to create the C(4) stereogenic center within this tricyclic molecular architecture.

Full text of DOI:10.1021/ol4007508

ORGANIC
LETTERS
2013
Vol. 15, No. 8
2050–2053
Asymmetric Synthesis of
(ꢀ)-Martinellic Acid
Stephen G. Davies,* Ai M. Fletcher, James A. Lee, Thomas J. A. Lorkin,
Paul M. Roberts, and James E. Thomson
Department of Chemistry, Chemistry Research Laboratory, University of Oxford,
Mansfield Road, Oxford OX1 3TA, U.K.
steve.davies@chem.ox.ac.uk
Received March 20, 2013
ABSTRACT
A high-yielding total asymmetric synthesis of (ꢀ)-martinellic acid is reported. The conjugate addition of lithium (R)-N-allyl-N-(R-methyl-4-
methoxybenzyl)amide to tert-butyl (E)-3-[20-(N,N-diallylamino)-50-bromophenyl]propenoate and alkylation of the resultant β-amino ester have
been used as the key steps to install the C(9b) and C(3a) stereogenic centers, respectively, and a highly diastereoselective Wittig reaction/
intramolecular Michael addition was then used to create the C(4) stereogenic center within this tricyclic molecular architecture.
A variety of extracts from Amazonian Martinella plants
are used by local tribes to treat inflammation of the eye1
and are said to cure conjunctivitis caused by infection from
microorganisms such as Gram-positive and Gram-negative
bacteria.2 In 1995, Witherup isolated (ꢀ)-martinellic acid 1
and (þ)-martinelline 2 from the species Martinella iqui-
toensis and showed them to be responsible for this effect.3
The interesting medicinal properties of 1 and 2 combined
with their unique fused pyrroloquinoline structure have
spurred research into the synthesis of this tricyclic molecular
architecture,4 as well as numerous analogues,5 with several
(5) (a) Snider, B. B.; O’Hare, S. M. Tetrahedron Lett. 2001, 42, 2455.
(b) Hadden, M.; Nieuwenhuyzen, M.; Potts, D.; Stevenson, P. J.;
Thompson, N. Tetrahedron 2001, 57, 5615. (c) Fadel, F.; Titouani,
S. L.; Soufiaoui, M.; Ajamaya, H.; Mazzah, A. Tetrahedron Lett.
2004, 45, 5905. (d) Stohler, R.; Wahl, F.; Pfaltz, A. Synthesis 2005,
1431. (e) Stevenson, P. J.; Nieuwenhuyzen, M.; Osborne, D. ARKIVOC
2007, xi, 129. (f) Rahaman, H.; Shirai, A.; Miyata, O.; Naito, T.
Tetrahedron Lett. 2008, 49, 5789. (g) Davies, S. G.; Mujtaba, N.;
Roberts, P. M.; Smith, A. D.; Thomson, J. E. Org. Lett. 2009, 11, 1959.
(6) For asymmetric syntheses, see: (a) Ma, D.; Xia, C. F; Jiang, J. Q.;
Zhang, J. Org. Lett. 2001, 3, 2189. (b) Ikeda, S.; Shibuya, M.; Iwabuchi,
Y. Chem. Commun. 2007, 504. (c) Shirai, A.; Miyata, O.; Tohnai, N.;
Miyata, M.; Procter, D. J.; Sucunza, D.; Naito, T. J. Org. Chem. 2008,
73, 4464. (d) Naito, T. Pure Appl. Chem. 2008, 80, 717.
(1) Gentry, A.; Cook, K. J. Ethnopharmacology 1984, 11, 337.
(2) Boralkar, A.; Dindore, P.; Fule, R.; Bangde, B.; Albel, M.; Saoji,
A. Indian J. Ophthalmol. 1989, 37, 94.
(3) Witherup, K. M.; Ransom, R. W.; Graham, A. C.; Bernard,
A. M.; Salvatore, M. J.; Lumma, W. C.; Anderson, P. S.; Pitzenberger,
S. M.; Varga, S. L. J. Am. Chem. Soc. 1995, 117, 6682.
(4) (a) Lovely, C. J.; Mahmud, H. Tetrahedron Lett. 1999, 40, 2079.
(b) Snider, B. B.; Ahn, Y.; Foxman, B. M. Tetrahedron Lett. 1999, 40,
+
3339. (c) Nyerges, M.; Fejes, I.; Toke, L. Tetrahedron Lett. 2000, 41,
(7) For racemic syntheses, see: (a) Snider, B. B.; Ahn, Y.; O‘Hare, S.
M. Org. Lett. 2001, 3, 4217. (b) Powell, D. A.; Batey, R. A. Org. Lett.
2002, 4, 2913. (c) Xia, C. F.; Heng, L. S.; Ma, D. Tetrahedron Lett. 2002,
43, 9405.
7951. (d) Hadden, M.; Nieuwenhuyzen, M.; Osborne, D.; Stevenson,
P. J.; Thompson, N. Tetrahedron Lett. 2001, 42, 6417. (e) Mahmud, H.;
Lovely, C. J.; Dias, H. V. R. Tetrahedron 2001, 57, 4095. (f) He, Y.;
Mahmud, H.; Wayland, B. R.; Dias, H. V. R.; Lovely, C. J. Tetrahedron
(8) For asymmetric syntheses, see: (a) Ma, D.; Xia, C.; Jiang, J.;
Zhang, J.; Tang, W. J. Org. Chem. 2003, 68, 442. (b) Badarinarayana, V.;
Lovely, C. J. Tetrahedron Lett. 2007, 48, 2607. (c) Yoshitomi, Y.; Arai,
H.; Makino, K.; Hamada, Y. Tetrahedron 2008, 64, 11568.
(9) For racemic syntheses, see: (a) He, Y.; Moningka, R.; Lovely,
C. J. Tetrahedron Lett. 2005, 46, 1251. (b) He, Y.; Mahmud, H.;
Moningka, R.; Lovely, C. J.; Dias, H. V. R. Tetrahedron 2006, 62,
8755. (c) Miyata, O.; Shirai, A.; Yoshino, S.; Nakabayashi, T.; Takeda,
Y.; Kiguchi, T.; Fukumoto, D.; Ueda, M.; Naito, T. Tetrahedron 2007,
63, 10092. (d) Ueda, M.; Kawai, S.; Hayashi, M.; Naito, T.; Miyata, O.
J. Org. Chem. 2010, 75, 914.
ꢀ
ꢀ
+
Lett. 2002, 43, 1171. (g) Viranyi, A.; Nyerges, M.; Blasko, G.; Toke, L.
ꢀ
+
Synthesis 2003, 2655. (h) Nyerges, M.; Viranyi, A.; Toke, L. Heterocycl.
Commun. 2003, 9, 239. (i) Yadav, J. S.; Subba Reddy, B. V.; Sunitha, V.;
Srinivasa Reddy, K.; Ramakrishna, K. V. S. Tetrahedron Lett. 2004, 45,
7947. (j) Hadden, M.; Nieuwenhuyzen, M.; Osborne, D.; Stevenson,
P. J.; Thompson, N.; Walker, A. D. Tetrahedron 2006, 62, 3977. (k) Ng,
P. Y.; Masse, C. E.; Shaw, J. T. Org. Lett. 2006, 8, 3999. (l) Miyata, O.;
Shirai, A.; Yoshino, S.; Takeda, Y.; Sugiura, M.; Naito, T. Synlett 2006,
893. (m) Zhang, Z.; Zhang, Q.; Yan, Z.; Liu, Q. J. Org. Chem. 2007, 72,
9808. (n) Neuschl, M.; Bogdal, D.; Potacek, M. Molecules 2007, 12, 49.
(o) Comesse, S.; Sanselme, M.; Daıch, A. J. Org. Chem. 2008, 73, 5566.
r
10.1021/ol4007508
Published on Web 04/04/2013
2013 American Chemical Society

total6,7 and formal8,9 syntheses of 1 and 2 having been
reported to date (Figure 1).10
yield and >99:1 dr. The configuration of the newly formed
C(3)-stereogenic center within 7 was assigned by reference
to our well established transition state mnemonic for this
class of reactions.13 Subsequent deprotonation of 7 with
LDA followed by the addition of methyl bromoacetate
gave 8 in 81% isolated yield and >98:2 dr (Scheme 1); the
stereochemical outcome of this reaction was initially as-
signed by reference to analogous alkylations,11,14 and the
absolute configuration within 8 was later confirmed un-
ambiguously by single crystal X-ray diffraction analysis of
a derivative.
As part of our ongoing research program concerning the
conjugate addition of enantiopure lithium amides,11 and in
particular the application of this methodology to the total
asymmetric synthesis of natural products,12 we envisaged
that the conjugate addition of lithium (R)-N-allyl-N-(R-
methyl-4-methoxybenzyl)amide 6 to tert-butyl (E)-3-[20-
(N,N-diallylamino)-50-bromophenyl]propenoate 5 could be
used as the key stereodefining step in the total synthesis of the
tricyclic core within (ꢀ)-martinellic acid 1. Herein we report
our investigations within this area, which culminate in the
total asymmetric synthesis of (ꢀ)-martinellic acid 1.
Scheme 1
Figure 1. (ꢀ)-Martinellic acid 1 and (þ)-martinelline 2.
R,β-Unsaturated ester 5 was prepared from Heck cou-
pling of 2-iodo-4-bromoaniline3 withtert-butylacrylate to
give 4, which was bis-N-allyl protected upon treatment
with excess allyl iodide and K3PO4 in acetone at reflux to
give 5 in 90% yield (from 3) and >99:1 dr. Conjugate
addition of lithium amide (R)-6 to R,β-unsaturated ester 5
gave the corresponding β-amino ester 7 in quantitative
Treatment of 8 with Pd(PPh3)4 and N,N-dimethylbarbi-
turic acid(DMBA) proceededtogive9, thentreatment of 9
with 10 mol % PhCO2H in PhMe at reflux for 16 h gave
complete conversion to tricycle 10. Attempted isolation of
10 gave poor mass return, although it was found that
treatment of 10 with Boc2O gave 11 in 49% yield (from 8)
after the three step procedure (Scheme 2). The relative
configuration within 11 was unambiguously established by
single crystal X-ray diffraction analysis (Figure 2),15 with
the absolute (3aR,9bS,RR)-configuration within 11 being
assigned from the known configuration of the R-methyl-4-
methoxybenzyl fragment. Furthermore, the determination
of a Flack x parameter16 of 0.011(8) for the crystal
structure of 11 allowed its absolute configuration to be
confirmed. This analysis also secured the assigned absolute
configurations within intermediates 7ꢀ10.
(10) For a review, see: Lovely, C. J.; Bararinarayana, V. Curr. Org.
Chem. 2008, 12, 1431.
(11) For reviews, see: (a) Davies, S. G.; Smith, A. D.; Price, P. D.
Tetrahedron: Asymmetry 2005, 16, 2833. (b) Davies, S. G.; Fletcher,
A. M.; Roberts, P. M.; Thomson, J. E. Tetrahedron: Asymmetry 2012,
23, 1111.
(12) For recent examples from this laboratory, see: (a) Abraham, E.;
Candela-Lena, J. I.; Davies, S. G.; Georgiou, M.; Nicholson, R. L.;
ꢀ
ꢀ
Roberts, P. M.; Russell, A. J.; Sanchez-Fernandez, E. M.; Smith, A. D.;
Thomson, J. E. Tetrahedron: Asymmetry 2007, 18, 2510. (b) Abraham,
E.; Davies, S. G.; Millican, N. L.; Nicholson, R. L.; Roberts, P. M.;
Smith, A. D. Org. Biomol. Chem. 2008, 6, 1655. (c) Davies, S. G.;
Fletcher, A. M.; Roberts, P. M.; Smith, A. D. Tetrahedron 2009, 65,
10192. (d) Davies, S. G.; Hughes, D. G.; Price, P. D.; Roberts, P. M.;
Russell, A. J.; Smith, A. D.; Thomson, J. E.; Williams, O. M. H. Synlett
2010, 567. (e) Davies, S. G.; Ichihara, O.; Roberts, P. M.; Thomson, J. E.
Tetrahedron 2011, 67, 216. (f) Bagal, S. K.; Davies, S. G.; Fletcher,
A. M.; Lee, J. A.; Roberts, P. M.; Scott, P. M.; Thomson, J. E.
Tetrahedron Lett. 2011, 52, 2216. (g) Bentley, S. A.; Davies, S. G.; Lee,
J. A.; Roberts, P. M.; Thomson, J. E. Org. Lett. 2011, 13, 2544. (h)
Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E.; West, C. J.
Tetrahedron Lett. 2011, 52, 6477. (i) Davies, S. G.; Fletcher, A. M.; Lee,
J. A.; Roberts, P. M.; Russell, A. J.; Taylor, R. J.; Thomson, A. D.;
Thomson, J. E. Org. Lett. 2012, 14, 1672. (j) Davies, S. G.; Lee, J. A.;
Roberts, P. M.; Stonehouse, J. P.; Thomson, J. E. Tetrahedron Lett.
2012, 53, 1119. (k) Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson,
J. E.; West, C. J. Tetrahedron 2012, 68, 4302. (l) Brock, E. A.; Davies,
S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E. Org. Lett. 2012, 14,
4278. (m) Davies, S. G.; Lee, J. A.; Roberts, P. M.; Stonehouse, J. P.;
Thomson, J. E. J. Org. Chem. 2012, 77, 7028. (n) Davies, S. G.; Lee, J. A.;
Roberts, P. M.; Stonehouse, J. P.; Thomson, J. E. J. Org. Chem. 2012,
Chemoselective reduction of 11 with LiAl(OtBu)3H pro-
ceeded cleanly to give a single diastereoisomeric hemiaminal
12 [of unknown configuration at C(4)] in quantitative yield,
without any detectable reduction of the amide functionality
(13) Costello, J. F.; Davies, S. G.; Ichihara, O. Tetrahedron:
Asymmetry 1994, 5, 1999.
(14) Davies, S. G.; Walters, I. A. S. J. Chem. Soc., Perkin Trans. 1
1994, 1129.
(15) Crystallographic data (excluding structure factors) for the struc-
tures of 11 and 15 have been deposited with the Cambridge Crystal-
lographic Data Centre as supplementary publication numbers CCDC
926034 and 926035, respectively.
(16) (a) Flack, H. D. Acta Crystallogr, Sect. A 1983, 39, 876. (b)
Flack, H. D.; Bernardinelli, G. J. Appl. Crystallogr. 2000, 33, 1143.
ꢀ
77, 9724. (o) Davies, S. G.; Fletcher, A. M.; Lebee, C.; Roberts, P. M.;
Thomson, J. E.; Yin, J. Tetrahedron 2013, 69, 1369. (p) Davies, S. G.;
Fletcher, A. M; Foster, E. M; Lee, J. A; Roberts, P. M.; Thomson, J. E.
J. Org. Chem. 2013, 78, 2500.
Org. Lett., Vol. 15, No. 8, 2013
2051

Scheme 2
Scheme 3
Figure 2. X-ray crystal structure of 11 (selected H atoms are
omitted for clarity).
at C(2). Treatment of 12 with ylid 13 in PhMe at 80 °C for
3 days installed the final stereogenic center required for the
synthesis of (ꢀ)-martinellic acid 1 and gave 14 as a single
diastereoisomer in 75% isolated yield. N-Boc deprotection
of 14 upon treatment with HCl in MeOH then gave 15 in
73% isolated yield. The relative configuration within 15 was
unambiguously established by single crystal X-ray diffrac-
tion analysis (Figure 3),15 and the absolute (3aS,4S,9bS,RR)-
configuration within 15 was assigned by reference to the
known configuration of the R-methyl-4-methoxybenzyl
fragment; the determination of a Flack x parameter16 of
0.014(9) for the crystal structure of 15 allowed this assign-
ment to be confirmed. Attempted N(1)-deprotection of 15
was not successful due to difficulties in the isolation of the
product. However, N(1)-deprotection of 14 upon treatment
with CAN gave 16, then reduction of 16 with BH3 proceeded
to give amine 17 (after decomplexation of BH3 upon heating
a solution of the intermediate complex in MeOH at reflux); in
this case 17 was isolated in 60% overall yield (from 14) and
>99:1 dr after chromatographic purification (Scheme 3).
N-Boc protection of the N(1) atom within 17 upon
treatment with Boc2O, followed by O-tosylation of 18 gave
Figure 3. X-ray crystal structure of 15 (selected H atoms are
omitted for clarity).
19 in 69% yield (from 17), thentreatment of 19withNaCN
in N-methyl-2-pyrrolidinone (NMP) gave 20 in 86% yield
and >99:1 dr (Scheme 4).
Carbonylation17 of 20 upon treatment with CO (1 atm),
Pd(OAc)2, Xantphos and Et3N in MeOH at 70 °C for 48 h
gave 21 in 69% yield. Subsequent reduction of the nitrile
group18 within 21 upon treatment with NiCl2 H2O, NaBH4
3
and Boc2O in MeOH at 0 °C gave 22 in 91% yield.
Deprotection of the three N-Boc groups within 22 upon
treatment with methanolic HCl gave “Ma’s intermediate”6a
23 in quantitative yield and >99:1 dr, completing a formal
(17) Martinelli, J. R.; Watson, D. A.; Freckmann, D. M. M.; Barder,
T. E.; Buchwald, S. L. J. Org. Chem. 2008, 73, 7102.
(18) Caddick, S.; Judd, D. B.; de K. Lewis, A. K.; Reich, M. T.;
Williams, M. R. V. Tetrahedron 2003, 59, 5417.
2052
Org. Lett., Vol. 15, No. 8, 2013

Scheme 4
Scheme 5
synthesis of (ꢀ)-martinellic acid 1 {in 6.0% yield over
17 steps from commercially available starting materials;
[R]D ꢀ48.7 (c 0.3 in MeOH); lit.6a [R]D ꢀ49.9 (c 1.25
in MeOH)}. Finally, 23 was converted into (ꢀ)-martinellic
acid 1 according to a literature procedure:6a in our hands,
20
20
application of this protocol gave 1 TFA in 22% yield. The
spectroscopic data for this sample of (ꢀ)-martinellic acid
3
20
1, including its specific rotation {[R]D ꢀ118 (c 0.3 in
MeOH); lit.3 for sample isolated from natural source
[R]D ꢀ8.5 (c 0.01 in MeOH); lit.6a [R]D ꢀ112.7 (c 0.31 in
20
MeOH); lit.6b [R]D ꢀ164.3 (c 0.14 in MeOH); lit.6c
29
23
[R]D ꢀ164.8 (c 0.33 in MeOH)}, were consistent with
literature data (Scheme 5).
In conclusion, the diastereoselective conjugate addition of
lithium (R)-N-allyl-N-(R-methyl-4-methoxybenzyl)-amide
to tert-butyl (E)-3-[20-(N,N-diallylamino)-50-bromophenyl]-
propenoate and alkylation of the resultant β-amino ester
have been used as the key steps to install correct stereo-
chemistry for the C(9b) and C(3a) stereogenic centers
within (ꢀ)-martinellic acid, respectively. A diastereoselec-
tive Wittig reaction/intramolecular Michael addition was
then used to create the final C(4) stereogenic center. After
further elaboration, (ꢀ)-martinellic acid was isolated as its
trifluoroacetate salt in 20steps and 1.3% overall yield from
commercially available starting materials.
ꢀ
Acknowledgment. We thank Veronique Gouverneur
and Stefan Verhoog for assistance with purification of
1 TFA by preparative HPLC.
3
Supporting Information Available. Experimental pro-
cedures, characterization data, copies of 1H and 13C NMR
spectra, and crystallographic information files (for struc-
tures CCDC 926034 and 926035). This material is available
free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 8, 2013
2053