Total synthesis of ent-lepadin F and G by a tandem ene-yne-ene ring closing metathesis

Article abstract of DOI:10.1021/jo7027079

(Chemical Equation Presented) The first total synthesis of the decahydroquinoline-alkaloids lepadin F and G is described. As key steps, the decahydroquinoline skeleton has been synthesized by utilizing a tandem ene-yne-ene ring closing metathesis of an acyclic precursor followed by a stereoselective hydrogenation of the resulting diene moiety. The selectivity of these two steps was achieved by a well-directed hydroxyl protection strategy. The synthesized compounds were found to be enantiomers of natural lepadin F and G, consequently the absolute configuration of the natural compounds could be assigned.

Full text of DOI:10.1021/jo7027079

Total Synthesis of ent-Lepadin F and G by a Tandem
Ene-Yne-Ene Ring Closing Metathesis
Alexander Niethe, Dirk Fischer, and Siegfried Blechert*
Institut fu¨r Chemie, Technische UniVersita¨t Berlin, Strasse des 17. Juni 135, D-10623 Berlin, Germany
blechert@chem.tu-berlin.de
ReceiVed December 20, 2007
The first total synthesis of the decahydroquinoline-alkaloids lepadin F and G is described. As key steps,
the decahydroquinoline skeleton has been synthesized by utilizing a tandem ene-yne-ene ring closing
metathesis of an acyclic precursor followed by a stereoselective hydrogenation of the resulting diene
moiety. The selectivity of these two steps was achieved by a well-directed hydroxyl protection strategy.
The synthesized compounds were found to be enantiomers of natural lepadin F and G, consequently the
absolute configuration of the natural compounds could be assigned.
Introduction
Lepadins are members of decahydroquinoline-alkaloids that
were found in marine sources. Lepadin A, B, and C where
isolated in the early 1990s from the North Sea tunicate ClaVelina
lepadiformis. These compounds have shown remarkable effects
against human cancer cells.1 In 2002 lepadins D-F were
discovered by Wright and Ko¨nig2 from tunicates of the genus
Didemnum, and Caroll and co-workers3 have isolated lepadins
F-H from Aplidium tabascum. Biological studies on lepadins
D-F have shown low cytotoxicity but have shown significant
and selective activity against malaria causing plasmodia and
some trypanosomes, which are the main pathogens of sleeping
sickness.2 Due to the present lack of effectual prophylaxis and
curing therapy for these diseases, lepadins are important targets
in drug development.
FIGURE 1. Proposed structures of lepadin F (1) and G (2).
As a key step in our synthesis, we planned the construction
of the decahydroquinoline-skeleton of the target structures by
a tandem ene-yne-ene ring closing metathesis6 (RCM) of the
precursor 5 (Scheme 1) followed by a stereoselective hydro-
In spite of the pharmacological potential only a few efforts
have been made toward the total synthesis of lepadins.4,5
Presently, no synthesis of lepadin F and G (Figure 1) is
described, and prior to our work their absolute configuration
has not been determined. Herein we describe the first total
synthesis of lepadin F and G.
(4) (a) Toyooka, N.; Okumura, M.; Takahata, H. J. Org. Chem. 1999,
64, 2182-2183. (b) Ozawa, T.; Aoyagi, S.; Kibayashi, C. Org. Lett. 2000,
2, 2955-2958. (c) Ozawa, T.; Aoyagi, S.; Kibayashi, C. J. Org. Chem.
2001, 66, 3338-3347. (d) Kalai, C.; Tate, E.; Zard, S. Z. Chem. Commun.
2002, 1430-1431. (e) Mena, M.; Bonjoch, J. Tetrahedron 2005, 8264-
8270; (f) Mena, M.; Valls, N.; Borregan, M.; Bonjoch, J. Tetrahedron 2006,
(9166-9173). (g) Barbe, G.; Charette, A. Abstract of Papers, 232nd
National Meeting of the American Chemical Society, San Francisco, CA,
Sept 10-14, 2006; American Chemical Society: Washington, DC, 2006;
ORGN-747. (h) Slafer, B.; et al. Abstract of Papers, 227th National Meeting
of the American Chemical Society, Anaheim, CA, March 28-April 1, 2004;
American Chemical Society: Washington, DC, 2004; ORGN-396.
(5) (a) Pu, X.; Ma, D. Angew. Chem., Int. Ed. 2004, 43, 4222-4225.
(b) Pu, X.; Ma, D. J. Org. Chem. 2006, 71, 6562-6572.
(1) (a) Steffan, B. Tetrahedron 1991, 47, 8729. (b) Kubanek, J.; Williams,
D. E.; Silva, E. D. d.; Allen, T.; Anderson, R. J. Tetrahedron Lett. 1995,
36, 6189-6192.
(2) Wright, A. D.; Goclik, E.; Ko¨nig, G. M.; Kaminsky, R. J. Med. Chem.
2002, 45, 3067-3072.
(3) Davis, R. A.; Carroll, A. R.; Quinn, R. J. J. Nat. Prod. 2002, 65,
454-457.
10.1021/jo7027079 CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/22/2008
3088
J. Org. Chem. 2008, 73, 3088-3093

Total Synthesis of ent-Lepadin F and G
SCHEME 1. Retrosynthesis
SCHEME 2. Tandem RCM of 5, Alternative Reaction
Paths
Results and Discussion
For the synthesis of 5 we chose commercially available
L-alanine as starting material. Esterification with methanol and
reductive amination with 4-anisaldehyde led to the chiral
building block 9 (Scheme 3). Following a method described
by Knochel et al.9 further condensation with cis-4-hexenal10 and
a copper-catalyzed addition of benzyl propargyl ether to the
intermediate iminium species furnished a 1:2 diastereomeric
mixture of propargylamines 10 and 11, which could be separated
after reduction with LiAlH4 and column chromatography of the
resulting alcohols 12 and 13.
In initial studies7b we were able to perform the three-
component-coupling with an increased diastereomeric ratio of
1:8 (10:11) utilizing R-QUINAP7b as the chiral ligand for the
copper catalyst. But during the development of the synthetic
concept we found that looking beyond the synthesis of lepadin
F and G, the synthesis of lepadin B and other lepadins would
be accessible from diastereomer 11. This is why we decided
not to perform two single diastereoselective steps toward 10
and 11 but rather to synthesize both substrates in one step with
subsequent chromatographic separation. Considering the high
costs of chiral ligands, this procedure seemed to us to be the
more economical way. Our attempts toward lepadin B and other
lepadins continuing from 13 are still in progress and will be
reported soon. With isolated 12 in hands we proceeded with
the synthesis of lepadin F and G. Therefore alcohol 12 was
further converted into aldehyde 14 by Swern oxidation in 99%
yield. Addition of vinylmagnesium chloride at -78 °C finally
yielded allylic alcohol 5 as a single diastereomer.
When the metathesis precursor 5 was exposed to catalyst Ru-
211 (Scheme 4) in dichloromethane at room temperature or at
40 °C no reaction occurred. For experiments in toluene at 80
°C we chose the very stable catalyst Ru-312 to avoid catalyst
decomposition at higher temperatures. We discovered that
although slow heating of a solution of catalyst and substrate
did not drive the reaction to completion after 1 day, the addition
of dissolved catalyst to a hot solution of the substrate resulted
in complete conversion after 3 h. Under these conditions
hexahydroquinoline 4 was obtained in 62% yield. We examined
other catalysts under identical reaction conditions. Surprisingly,
genation of the resulting hexahydroquinoline 4 with concomitant
removal of a benzyl and a p-methoxybenzyl protecting group.
We envisioned that a bulky silyl group on the hydroxyl group
of 4 would allow control of stereochemistry in the hydrogenation
step.
From 3, attaching the side chain on the hydroxylmethyl
moiety, inversion of the configuration of the ring hydroxyl
group, and esterification with either octenoic acid or octadienoic
acid would finally lead to lepadin F (1) and G (2).
For the synthesis of the eight-carbon side chain of lepadin F
and G, we projected a concept that allows an enantioselective
construction of both enantiomers of the secondary alcohol.
Comparison of spectroscopic and chiroptical data of synthesized
materials with the data available for natural products would then
allow the determination of the actual unknown configuration.
On closer examination of the projected metathesis step, two
different reaction pathways could be envisioned (Scheme 2):
(a) metathesis may initiate at the terminal double bond to
produce Ru-carbene intermediate 6, which on two consecutive
RCMs gives rise to the desired bicycle 4 or (b) metathesis may
initiate on the disubstituted alkenyl moiety to produce Ru-
carbene species 7. Tandem RCM would then lead to the5,7
bicycle 8. Therefore we intended to leave the allylic hydroxyl
group unprotected in the metathesis reactions so that it could
exert a coordinative effect in the initial catalyst attack favoring
pathway (a) in addition to the preference of attack on mono-
substituted alkenes over disubstituted alkenes. Similar effects
have been reported earlier by us7 and others8 and should be an
effective strategy to control the regiochemistry at this step.
(8) (a) BouzBouz, S.; Simmons, R.; Cossy, J. Org. Lett 2004, 7, 3465-
3467. (b) Hoye, T. R.; Zhao, H. Org. Lett. 1999, 1, 1123-1125.
(9) (a) Dube, H.; Gommermann, N.; Knochel, P. Synthesis 2004, 12,
2015-2025. (b) Gommermann, N.; Koradin, C.; Polborn, K.; Knochel, P.
Angew. Chem., Int. Ed. 2003, 42, 5763-5766.
(10) cis-4-Hexenal was synthesized by Swern oxidation from com-
mercially available cis-4-hexenol and was used subsequently without further
purification.
(11) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(12) (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, H. J.
Am. Chem. Soc. 2000, 122, 8168. (b) Gesslar, S.; Blechert, S. Tetrahedron
Lett. 2000, 41, 9973. (c) Gessler, S.; Randl, S.; Blechert, S. Tetrahedron
Lett. 2000, 41, 9973-9976.
(6) For reviews about ene-yne metathesis see: (a) Diver, S. T.; Giessert,
A. J. Chem. ReV. 2004, 104, 1317-1382. (b) Randl, S.; Blechert, S. In
Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, 2003;
Vol. 2, pp 151-175. For selected examples see: (c) Fukumoto, H.;
Takahashi, K.; Ishihara, J.; Hatakeyama, S. Angew. Chem., Int. Ed. 2006,
45, 2731-2734. (d) Honda, T.; Namiki, H.; Kaneda, K.; Mizutani, H. Org.
Lett. 2004, 6, 87-89. (e) Zuercher, W. J.; Hashimoto, M.; Grubbs, R. H.
J. Am. Chem. Soc. 1996, 118, 6634-6640.
(7) (a) Michaelis, S.; Blechert, S. Org. Lett 2005, 7, 5513-5516. (b)
Fischer, D. Thesis, Technical University Berlin, Berlin, 2005.
J. Org. Chem, Vol. 73, No. 8, 2008 3089

Niethe et al.
SCHEME 3. Synthesis of Metathesis Precursor 5
SCHEME 4. Transformation of 5 into Decahydroquinoline 3
metathesis with less stable Ru-113 furnished 4 without significant
formation of byproducts as happened during reaction with Ru-2
and Ru-3. At an optimal temperature of 60 °C using Ru-1 in
dichloroethane we were able to achieve an increased yield of
90%. At room temperature the metathesis reaction did not
proceed with this catalyst either.
with Grignard reagents starting from enantiopure epichloro-
hydrin. Access to both enantiomers of the product as mentioned
above is possible either by changing the sequence of Grignard
addition or by using the opposite enantiomer of the starting
material. We decided to start the synthesis with commercially
available (S)-epichlorohydrin.
Having established the tandem ene-yne-ene RCM, we next
set out to perform the envisioned stereoselective hydrogenation
of hexahydroquinoline 4. Treatment with TBDMSCl and
imidazole in dichloromethane generated protected alcohol 15
(Scheme 4), which was directly used in the following step.
Hydrogenation with a Pd/C catalyst at 10 bar H2 pressure
resulted in complete reduction of the diene moiety with
concomitant cleavage of the PMB-protecting group on the ring
nitrogen atom. The benzyl ether, however, was not cleaved in
this step. Subsequent reaction with Boc2O at room temperature
followed by a second hydrogenation step with Pd/C yielded
decahydroquinoline 3 as colorless crystals in 50% yield over
four steps. From a chloroform/heptane solution single-crystals
were obtained. The X-ray diffraction analysis confirmed the
postulated structure as shown in Figure 2.
Following this method (S)-epichlorohydrin 16 (Scheme 5)
was converted into (4S)-hept-1-en-4-ol 17 by Grignard addition
of ethylmagnesium bromide, subsequent epoxide formation with
NaOH, and second Grignard addition of vinylmagnesium
bromide. Comparison of the optical rotation of the synthesized
Elaboration of the C-5 Side Chain
Recently14 we described the synthesis of enantiopure hept-
1-en-4-ol by a 2-fold copper-catalyzed epoxide ring-opening
(13) Nguyen, S. T.; Johnson, L. K.; Grubbs, R. H.; Ziller, J. W. J. Am.
Chem. Soc. 1992, 114, 3974.
(14) Holub, N.; Neidho¨fer, J.; Blechert, S. Org. Lett. 2005, 7, 1227-
1229.
FIGURE 2. ORTEP-structure of 3 as determined by X-ray diffraction.
3090 J. Org. Chem., Vol. 73, No. 8, 2008

Total Synthesis of ent-Lepadin F and G
SCHEME 5. Synthesis of the C-5 Side Chain
SCHEME 6. Synthesis of Lepadin F and G
material with literature data15 confirmed the retention of
configuration. Alcohol 17 was next converted into its MOM-
ether 18 by reaction with MOMCl in dichloromethane. Subse-
quent hydroboration with a large excess of BH3-THF and
oxidative workup led to alcohol 19. The Mitsunobu reaction
with 1-phenyl-1H-tetrazole-5-thiole proceeded smoothly to form
thioether 20 in 80% yield. Subsequent oxidation with mCPBA
resulted in sulfonee 21, which could be used for a side chain
attachment by a Julia-Kocienski olefination, as has already been
employed in the synthesis of lepadin D, E, and H.5
With sulfone 21 in hands we proceeded with the synthesis
of lepadin F and G. Swern oxidation of intermediate 3 gave
aldehyde 22 (Scheme 6), which was directly used in the Julia-
Kocienski olefination with 21, which proceeded in 66% yield.
Hydrogenation of the C-C double bond in 23 and subsequent
cleavage of the TBDMS-ether furnished alcohol 24. Complete
inversion of the C-3 carbinol stereocenter was achieved by Dess-
Martin oxidation and reduction of the resulting ketone with
NaBH4 at -55 °C in methanol. The reaction product 25 was
finally used in a Yamaguchi esterification16 with 2E-octenoic
acid and 2E,4E-octadienoic acid17 to furnish lepadin F 1 and
lepadin G 2 each in 50% yield after cleavage of the Boc- and
MOM-protecting group with trifluoroacetic acid.
The 1H NMR and 13C NMR spectroscopic data of the
synthetic materials were in complete agreement with the
literature data. Comparison of the optical rotation identified 2
as the enantiomer of natural lepadin G. 1 could also be
determined as an enantiomer of lepadin F after critical com-
parison with the simultaneously published data by Davis and
Ko¨nig: Davis described lepadin F as red oil with positive optical
rotation (R ) 5.5° in CH2Cl2) and Ko¨nig isolated a colorless
oil with a negative value (R ) -1.5° in CHCl3). Our synthesized
material was also colorless with positive values (R ) 1.5° in
CH2Cl2 and 8.8° in CHCl3). It seems likely that the alkaloid
should not be a red oil and the different rotation of Davis could
be caused by traces of impurities. As a conclusion of these
comparisons and the accordance of NMR data, 1 is also the
enantiomer of natural lepadin F. Consequently, the absolute
configuration of natural lepadin F and G could be assigned as
2R,3R,4aS,5S,8aR,5′R.
In conclusion, we have successfully performed the first total
synthesis of lepadin F and G in a longest linear sequence of 19
steps with 2% overall yield. During the linear path only seven
chromatographic purifications were necessary. As key steps the
decahydroquinoline skeleton was built from an acyclic precursor
by a tandem ene-yne-ene ring closing metathesis and a
(15) Riediker, M.; Duthaler, R. O. Angew. Chem. 1989, 101, 488-490.
(16) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
(17) Coutrot, P.; Snoussi, M.; Savignac, P. Synthesis 1978, 133-134.
J. Org. Chem, Vol. 73, No. 8, 2008 3091

Niethe et al.
71.5 (CH2), 80.7 (C), 87.2 (C), 113.9 (2 × CH), 124.9 (CH), 127.8
(2 × CH), 128.0 (2 × CH), 128.3 (CH), 128.4 (CH), 129.2 (CH),
129.6 (CH), 132.3 (C), 137.5 (C), 158.6 (C). IR (ATR): ν ) 3457
(br m), 3010 (w), 2962 (m), 2934 (m), 2857 (m), 1611 (m), 1511
(s), 1454 (m), 1244 (s), 1072 (s), 1036 (s). MS (EI, 150 °C): m/z
(%) ) 420 (M+, <1), 390 (100), 352 (12), 121 (100), 91 (30).
HR-MS (C26H32NO2, M - CH3O): calcd 390.2433, found 390.2433.
Anal. Calcd for C27H35NO3: C, 76.92; H, 8.37; N, 3.32. Found:
C, 76.54; H, 8.56; N, 3.41.
stereoselective hydrogenation. The synthesized compounds were
identified as enantiomers of the natural products and the absolute
configuration of natural lepadin F and G were confirmed.
Additional attempts toward the synthesis of other lepadins
starting from allylic alcohol 13 are in progress and will be
reported soon.
Experimental Section
2S,4R-2-[[1-(3-(Benzyloxy)prop-1-ynyl)hex-4-enyl](4-meth-
oxybenzyl)amino]propionic Acid Methyl Ester (13). RF (hexane/
2S-2-[[1-(3-(Benzyloxy)prop-1-ynyl)-hex-4-enyl](4-methoxy-
benzyl)amino]propionic Acid Methyl Ester (10 and 11). A 21.49
g (219 mmol) sample of cis-4-hexenal, 29.09 g (199 mmol) benzyl
propargyl ether, and 48.90 g (219 mmol) of 9 were dissolved in
600 mL of toluene. The mixture was treated with 50 g of powdered
molecular sieves and 2.87 g (20 mmol) of CuBr and stirred 3 days
at room temperature (rt). Afterward the brown-green suspension
was filtered over celite and evaporated in vacuo. The residue was
redissolved in 400 mL of methyl tert-butyl ether and washed with
100 mL of water, 100 mL of 1 N HCl, and 100 mL of saturated
aqueous NaHCO3, and the solution was dried over Na2SO4 and
filtered. A 400 mL aliquot of hexane was added, and the mixture
was filtered over a short pad of silica and evaporated in vacuo to
give 84.13 g (94%) of a 1:2 diastereomeric mixture of 10 and 11.
1H NMR (500 MHz, CDCl3): δ (ppm) ) 1.22-1.23 (d, J ) 7.2
Hz, 1H), 1.39-1.40 (d, J ) 7.2 Hz, 2H), 1.58-1.74 (m, 5H), 2.02-
2.25 (m, 2H), 3.44-3.46 (m, 0.4 H), 3.58-3.61 (m, 0.6 H), 3.64-
3.70 (m, 4H), 3.72-3.96 (m, 5H), 4.21 (d, J ) 1.6 Hz, 0.7 H),
4.24 (d, J ) 1.6 Hz, 1.3 H), 4.61 (s, 0.7 H), 4.62 (s, 1.3 H), 5.26-
5.48 (m, 2H), 6.83-6.86 (m, 2H), 7.27-7.32 (m, 3H), 7.34-7.39
(m, 4 H). 13C NMR (125 MHz, CDCl3): δ (ppm) ) 12.8 (CH),
12.9 (CH), 13.4 (CH), 16.7 (CH), 23.8 (CH2), 23.9 (CH2), 34.7
(CH2), 34.9 (CH2), 49.2 (CH), 50.7 (CH2), 50.9 (CH2), 51.1 (CH),
51.2 (CH), 51.6 (CH), 54.7 (CH), 55.3 (CH), 57.1 (CH), 57.5 (CH2),
57.6 (CH2), 71.3 (CH2), 71.4 (CH2), 80.2 (C), 80.5 (C), 85.6 (C),
86.9 (C), 113.6 (CH), 113.7 (CH), 124.5 (CH), 124.7 (CH), 128.1
(CH), 128.1 (CH), 128.5 (CH), 128.5 (CH), 129.5 (CH), 129.6 (CH),
129.9 (CH), 131.8 (CH), 132.1 (CH), 137.6 (C), 137.6 (C), 158.6
(C), 158.7 (C), 173.6 (C), 174.6 (C). IR (ATR): ν ) 3065 (w),
3029 (w), 3009 (w), 2976 (w), 2948 (m), 2938 (m), 2855 (m), 2837
(m), 1734 (s), 1611 (m), 1511 (s), 1454 (m), 1244 (s). MS (EI,
130): m/z (%) ) 449, M+, <1), 116 (52), 390 (30), 380 (40), 121
(100), 91 (22). HR-MS (C28H35NO4): calcd 449.2566, found
449.2567. Anal. Calcd for C28H35NO4: C, 74.80; H, 7.85; N, 3.12.
Found: C, 74.64; H, 7.54; N, 2.97.
methyl tert-butyl ether ) 1:1) ) 0.40. [a]20 ) + 128.5° (c )
D
1
1.23, CHCl3). H NMR (500 MHz, CDCl3): δ (ppm) ) 1.14-
1.16 (d, J ) 6.6 Hz, 3H), 1.57-1.58 (m, 3H), 1.61-1.67 (m, 1H),
1.75-1.84 (m, 1H), 2.11-2.18 (m, 2H), 2.91 (br s, 1H), 3.08-
3.15 (m, 1H), 3.32-3.34 (d, J ) 7.9 Hz, 2H), 3.48-3.53 (dddd, J
) 1.7, 1.7, 6.2, 8.1 Hz, 1H), 3.57-3.60 (d, J ) 13.6 Hz, 1H),
3.77-3.81 (d, J ) 13.6 Hz, 1H), 3.80 (s, 3H), 4.26 (s, 2H), 4.64
(s, 2H), 5.25-5.32 (m, 1H), 5.39-5.47 (m, 1H), 6.85-6.87 (d, J
) 8.7 Hz, 2H), 7.20-7.26 (m, 2H), 7.28-7.34 (m, 1H), 7.35-
7.38 (m, 4H). 13C NMR (125 MHz, CDCl3): δ (ppm) ) 11.4 (CH3),
12.8 (CH3), 23.9 (CH2), 35.3 (CH2), 48.4 (CH), 49.9 (CH2), 54.0
(CH), 55.2 (CH3), 57.6 (CH2), 63.1 (CH2), 71.4 (CH2), 80.7 (C),
87.2 (C), 113.9 (CH), 124.9 (2 × CH), 127.8 (CH), 128.0 (2 ×
CH), 128.3 (2 × CH), 128.4 (CH), 129.0 (CH), 130.1 (CH), 131.3
(C), 137.5 (C), 158.6 (C). IR (ATR): ν ) 3458 (br m), 3010 (w),
2959 (m), 2934 (m), 2855 (m), 1611 (m), 1512 (s), 1245 (s), 1036
(s). MS (EI, 150 °C): m/z (%) ) 421 (M+, <1), 390 (80), 352
(12), 121 (100), 91 (28). HR-MS (C27H35NO3): calcd 421.2616,
found 421.2623. Anal. Calcd for C27H35NO3: C, 76.92; H, 8.37;
N, 3.32. Found: C, 76.83; H, 8.23; N, 3.00.
2S,3R,8aS-5-[(Benzyloxy)methyl]-1-(4-methoxybenzyl)-2-meth-
yl-1,2,3,7,8,8a-hexahydroquinolin-3-ol (4). A 6.71 g (15.00 mmol)
sample of 5 was dissolved in 500 mL of dichloroethane, the solution
was heated to 60 °C, and a solution of 1.23 g (1.50 mmol) of Ru-1
in 20 mL of dichloroethane was added at this temperature. The
mixture was stirred for 3 h at 60 °C, quenched with ethyl vinyl
ether, and evaporated in vacuo. Purification by chromatography in
hexane/EtOAc ) 8:2 gave 5.49 g (90%) 4 as a brown oil.
RF (hexane/EtOAc ) 6:4) ) 0.30. [a]20D ) -81.43° (c ) 1.02,
1
CHCl3). H NMR (500 MHz, CDCl3): δ (ppm) ) 0.88-0.91 (d,
J ) 6.8 Hz, 3H), 1.38-1.46 (m, 1H), 2.25-2.30 (m, 3H), 2.41-
2.44 (d, J ) 11.0 Hz, 1H), 2.94-2.99 (dq, J ) 1.7, 6.7 Hz, 1H),
3.08-3.11 (br d, J ) 12.0 Hz, 1H), 3.40-3.43 (d, J ) 13.9 Hz,
1H), 3.67-3.71 (m, 1H), 3.79 (s, 3H), 3.99-4.03 (d, J ) 13.9 Hz,
1H), 4.08-4.11 (d, J ) 11.5 Hz, 1H), 4.16-4.19 (d, J ) 11.5 Hz,
1H), 4.51 (s, 2H), 5.89-5.90 (m, 1H), 5.94-5.96 (m, 1H), 6.83-
6.87 (m, 2H), 7.23-7.31 (m, 3H), 7.32-7.36 (m, 4H). 13C NMR
(125 MHz, CDCl3): δ (ppm) ) 7.8 (CH3), 25.2 (CH2), 27.9 (CH2),
53.2 (CH2), 55.2 (CH3), 55.4, 55.6 (CH), 67.9 (CH), 70.9 (CH2),
72.1 (CH2), 113.8 (2× CH), 119.0 (CH), 127.5 (CH), 127.8 (2 ×
CH), 128.3 (2 × CH), 129.3 (2 × CH), 129.8 (CH, C-6), 131.9
(C), 132.2 (C), 138.0 (C), 138.3 (C), 158.6 (C). IR (ATR): ν )
3422 (br m), 2961 (m), 2930 (m), 2860 (m), 2833 (m), 1611 (m),
1511 (s), 1453 (m), 1244 (s), 1029 (s). MS (EI, 200 °C): m/z (%)
) 405 (M+, <1), 164 (32), 134 (10), 121 (100), 91 (44). HR-MS
(C26H31NO3): calcd 405.2303, found 405.2310. Anal. Calcd for
C26H31NO3: C, 77.01; H, 7.70; N, 3.45. Found: C, 76.91; H, 7.76;
N, 3.47.
2S,4S-2-[[1-(3-(Benzyloxy)prop-1-ynyl)hex-4-enyl](4-methoxy-
benzyl)amino]propionic Acid Methyl Ester (12) and 2S,4R-2-
[[1-(3-(Benzyloxy)prop-1-ynyl)hex-4-enyl](4-methoxybenzyl)-
amino]propionic Acid Methyl Ester (13). A 83.87 g (186 mmol)
sample of 10/11 was dissolved in 500 mL of THF, and 4.96 g (130
mmol) of LiAlH4 was added portionwise at -78 °C. The solution
was slowly warmed to rt overnight, then water was added carefully,
and the mixture was filtered over celite. The filtrate was extracted
with methyl tert-butyl ether, washed with saturated aqueous NaCl,
dried over Na2SO4 and evaporated in vacuo. After chromatography
in hexane/methyl tert-butyl ether ) 8:2, 20.89 g (27%) of 12 and
45.53 g (59%) of 13 were achieved as colorless oils.
2S,4S-2-[[1-(3-(Benzyloxy)prop-1-ynyl)hex-4-enyl](4-methoxy-
benzyl)amino]propionic Acid Methyl Ester (12). RF (hexane/
methyl tert-butyl ether ) 1:1) ) 0.29. [a]20D ) +19.9° (c ) 1.30,
2S,3R,4aR,5R,8aS-3-((tert-Butyldimethylsilanyl)oxy)-5-(hy-
droxymethyl)-2-methyloctahydroquinoline-1-carboxylic Acid tert-
Butyl Ester (3). A 1.34 g (2.50 mmol) sample of 15 was dissolved
in 25 mL of methanol, then 266 mg (0.25mmol) of Pd/C (10%)
was added, and the mixture was hydrogenated at 10 bar H2 pressure
for 2 days. The catalyst was filtered off, and the solution was
evaporated in vacuo. The residue was treated with 1.09 g (5.00
mmol) of Boc2O and 2.5 mL of dichloromethane, and the solution
was stirred 3 days at rt. Afterward the mixture was dissolved in
methyl tert-butyl ether, washed with water and saturated aqueous
1
CHCl3). H NMR (500 MHz, CDCl3): δ (ppm) ) 1.10-1.12 (d,
J ) 6.5 Hz, 3H), 1.59-1.61 (m, 4H), 1.67-1.76 (m, 1H), 2.11-
2.20 (m, 2H), 2.83 (br s, 1H), 3.14-3.22 (m, 1H), 3.32-3.45 (m,
2H), 3.59-3.63 (m, 1H), 3.73-3.74 (d, J ) 4.1 Hz, 2H), 3.80 (s,
3H), 4.25 (s, 2H), 4.63 (s, 2H), 5.28-5.35 (m, 1H), 5.42-5.51
(m, 1H), 6.84-6.86 (d, J ) 8.7 Hz, 2H), 7.22-7.25 (m, 2H), 7.28-
7.34 (m, 1H), 7.35-7.38 (m, 4H). 13C NMR (125 MHz, CDCl3):
δ (ppm) ) 12.8 (CH3), 13.8 (CH3), 24.1 (CH2), 33.9 (CH2), 48.1
(CH2), 53.2 (CH), 55.2 (CH3), 57.5 (CH2), 57.9 (CH), 63.9 (CH2),
3092 J. Org. Chem., Vol. 73, No. 8, 2008

Total Synthesis of ent-Lepadin F and G
NaHCO3, dried over Na2SO4, and filtered over a short pad of silica.
The filtrate was evaporated in vacuo, redissolved in 25 mL of
methanol, treated with 266 mg (0.25 mmol) of Pd/C (10%), and
stirred under a hydrogen atmosphere (15 bar) for 2 days. After
filtration of the catalyst and evaporation of the filtrate in vacuo,
chromatography in hexane/EtOAc ) 9:1 and 8:2 gave 517 mg (50%
over 3 steps) 3 as colorless crystals.
mg (0.113 mmol) of DMAP in 1 mL of toluene was added for 45
min, and the resulting solution was stirred an additional 18 h at rt.
The mixture was filtered over celite and evaporated in vacuo. The
residue was dissolved in 2 mL of dichloromethane, and the solution
was treated with 0.2 mL of TFA and stirred 1 h at rt. A 0.05 mL
aliquot of 5% aqueous NH3 was added, and the resulting solution
was stirred for 10 min. Then solid Na2SO4 was added, and the
mixture was filtered and evaporated in vacuo. Purification by
chromatograohy in DCM/MeOH/conc NH3 ) 15:1:0.1 gave 9 mg
(50%) lepadin F (1) as a colorless oil.
RF (hexane/EtOAc ) 6:4) ) 0.31; [a]20 ) +0.65° (c ) 0.76,
D
1
CHCl3). MP ) 122 °C. H NMR (500 MHz, CDCl3): δ (ppm) )
0.04 (s, 3H), 0.05 (s, 3H), 0.86 (s, 9H), 1.05-1.13 (dq, J ) 3.4,
12.9 Hz, 1H), 1.19-1.21 (d, J ) 6.8 Hz, 3H), 1.24-1.35 (m, 2H),
1.41-1.52 (m, 2H), 1.45 (s, 9H), 1.70-1.79 (m, 3H), 1.83-1.88
(ddd, J ) 7.3, 7.3, 14.6 Hz, 1H), 1.97-2.05 (m, 1H), 2.33-2.39
(dddd, J ) 4.4, 4.4, 4.4, 4.4, 8.0 Hz, 1H), 3.42-3.49 (m, 2H),
3.74-3.80 (m, 2H), 3.80-3.84 (m, 1H). 13C NMR (125 MHz,
CDCl3): δ (ppm) ) -4.8 (CH3), -4.7 (CH3), 18.0 (C), 19.5 (CH3),
22.8, 24.4 (CH2), 25.7 (3 × CH3), 26.0, 26.0 (CH2), 28.5 (3 ×
CH3), 31.6 (CH), 42.9 (CH), 53.5, 55.0 (CH), 65.0 (CH2), 70.4
(CH), 79.0 (C), 155.6 (C). IR (ATR): ν ) 3441 (br m), 2953 (s),
2928 (s), 2857 (m), 1688 (s), 1666 (s), 1400 (s), 1365 (s), 1255
(s), 1080 (s). MS (EI, 180 °C): m/z (%) ) 413 (M+, <1), 300
(100), 282 (24), 256 (16), 182 (10), 91 (22). HR-MS (C22H43NO4-
Si): calcd 413.2961, found 413.2969. Anal. Calcd for C22H43NO4-
Si: C, 63.88; H, 10.48; N, 3.39. Found: C, 63.87; H, 10.45; N,
3.40.
RF (DCM/MeOH/conc NH3 ) 15:1:0.1) ) 0.13. [a]20D ) +8.8°
1
(c ) 0.25, CHCl3); [a]20 ) +1.5° (c ) 0.27, CH2Cl2). H NMR
D
(500 MHz, CDCl3): δ (ppm) ) 0.89 (t, J ) 6.9 Hz, 3H), 0.92 (t,
J ) 7.0 Hz, 3H), 0.87-0.93 (m, 1H), 1.01-1.03 (d, J ) 6.9 Hz,
3H), 1.11-1.50 (m, 22H), 1.60-1.71 (m, 3H), 1.73-1.88 (m, 3H),
2.06-2.13 (m, 1H), 2.17-2.23 (m, 2H), 2.88-2.94 (m, 1H), 3.07-
3.13 (q, J ) 6.5 Hz, 1H), 3.53-3.59 (m, 1H), 4.94 (br s, 1H),
5.88-5.92 (dt, J ) 15.6, 1.6 Hz, 1H), 6.98-7.05 (dt, J ) 15.5,
7.1 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) ) 14.0 (CH),
14.1 (CH), 18.3 (CH), 18.8 (CH2), 22.4 (CH2), 23.7 (CH2), 25.3
(CH2), 25.7 (CH2), 26.5 (CH2), 27.0 (CH2), 27.7 (CH2), 29.7 (CH2),
31.4 (CH2), 32.2 (CH2), 32.9 (CH2), 33.0 (CH2), 37.5 (CH2), 39.5
(CH), 39.8 (CH2), 47.2 (CH), 55.5 (CH), 71.1 (CH), 71.6 (CH),
121.2 (CH), 150.0 (CH) 166.5 (C). IR (ATR): ν ) 3313 (br w),
2954 (m), 2927 (s), 2856 (m), 1717 (m), 1653 (m), 1464 (m), 1264
(m), 1172 (m). MS (EI, 170 °C): m/z (%) ) 421 (M+, 2), 279
(70), 264 (50), 236 (60), 206 (22), 178 (100), 164 (28), 150 (48),
108 (40). HR-MS (C26H47NO3): calcd 421.3555, found 421.3557.
2S,3S,4aR,5R,8aS,5′S-Octa-2,4-dienonic Acid 5-(5-Hydroxy-
octyl)-2-methyldecahydroquinolin-3-yl Ester (2). Following the
same procedure as described for 1 gave 9 mg (50%) of lepadin G
(2) as a colorless oil.
2S,3R,4aR,5R,8aS,5′S-3-((tert-Butyldimethylsilanyl)oxy)-5-(5-
methoxyoct-1-enyl)-2-methyloctahydroquinoline-1-carboxylic Acid
tert-Butyl Ester (23). A 243 mg (0.66 mmol) sample of 21 was
dissolved in 7 mL of THF, and the solution was cooled to -78 °C.
Then 1.32 mL (0.66 mmol) of KHMDS (0.5 M in toluene) dissolved
in 1 mL of THF was added dropwise, and the resulting solution
was stirred for 45 min. Afterward 134 mg (0.33 mmol) of 22 in 3
mL of THF was added dropwise, and the reaction mixture was
allowed to warm to rt overnight. Then saturated aqueous NaCl was
added, and the mixture was extracted with ethyl acetate, dried over
Na2SO4, and evaporated in vacuo. Purification by chromatography
in hexane/methyl tert-butyl ether ) 9:1 gave 120 mg (66%) of 23
as a yellow oil.
RF (DCM/MeOH/conc NH3 ) 15:1:0.1) ) 0.21. [a]20D ) -14.5°
1
(c ) 0.27, CH2Cl2). H NMR (500 MHz, C6D6): δ (ppm) ) 0.72
(t, J ) 7.4 Hz, 3H), 0.77-0.86 (m, 1H), 0.89 (t, J ) 7.0 Hz, 3H),
1.06-1.07 (d, J ) 6.5 Hz, 3H), 1.10-1.19 (m, 5H), 1.22-1.36
(m, 12H), 1.38-1.48 (m, 3H), 1.54-1.68 (m, 3H), 1.73.1.85 (m,
3H), 2.12-2.19 (m, 1H), 2.75-2.86 (m, 2H), 3.38-3.43 (m, 1H),
5.02-5.05 (m, 1H), 5.64-5.64-5.72 (dt, J ) 14.3, 7.0 Hz, 1H),
5.90-5.97 (dd, J ) 15.2, 11.0 Hz, 1H), 5.95-5.99 (d, J ) 15.2
Hz, 1H), 7.53-7.59 (dd, J ) 15.2, 11.0 Hz, 1H). 13C NMR (125
MHz, C6D6): δ (ppm) ) 14.2 (CH), 15.0 (CH), 19.1 (CH), 19.8
(CH2), 22.6 (CH2), 24.6 (CH2), 26.0 (CH2), 26.4 (CH2), 26.6 (CH2),
27.6 (CH2), 27.9 (CH2), 30.7 (CH2), 33.9 (CH2), 34.0 (CH2), 35.6
(CH2), 38.6 (CH2), 40.4 (CH), 40.8 (CH2), 48.1 (CH), 56.3 (CH),
71.7 (CH), 72.0 (CH), 120.8 (CH), 144.6 (CH), 145.8 (CH), 167.1
(C). IR (ATR): ν ) 3313 (br w), 2955 (m), 2929 (s), 2857 (m),
1710 (m), 1642 (m), 1464 (m), 1247 (m), 1137 (m), 1000 (m). MS
(EI, 170 °C): m/z (%) ) 419 (M+, <1), 376 (10), 279 (100), 264
(44), 236 (48), 206 (20), 178 (44), 164 (12), 150 (22), 123 (20).
HR-MS (C26H45NO3): calcd 419.3399, found 419.3419.
RF (hexane/EtOAc ) 8:2) ) 0.33. [a]20 ) -7.0° (c ) 0.80,
D
1
CHCl3). H NMR (500 MHz, CDCl3): δ (ppm) ) 0.03 (s, 3H),
0.05 (s, 3H), 0.86 (s, 9H), 0.89-0.92 (t, J ) 7.0 Hz, 3H), 1.18-
1.19 (d, J ) 7.4 Hz, 3H), 1.24-1.41 (m, 7H), 1.44 (s, 9H), 1.49-
1.57 (m, 3H), 1.66-1.73 (m, 2H), 1.78-1.85 (ddd, J ) 7.0, 7.0,
14.3 Hz, 1H), 1.91-2.10 (m, 3H), 2.11-2.23 (m, 2H), 3.38 (s,
3H), 3.50-3.56 (m, 1H), 3.69-3.74 (m, 1H), 3.75-3.79 (m, 1H),
3.79-3.84 (m, 1H), 4.64 (s, 2H), 5.29-5.42 (m, 2H). 13C NMR
(125 MHz, CDCl3): δ (ppm) ) -4.8 (CH3), -4.7 (CH3), 14.3
(CH3), 18.0 (C), 18.5 (CH2), 19.4 (CH3), 24.6 (CH2), 25.3 (CH2),
25.7 (3 × CH3), 26.8 (CH2), 26.9 (CH2), 28.5 (CH2), 28.5 (3 ×
CH3), 34.3 (CH2), 35.8 (CH), 36.6 (CH2), 43.2 (CH), 53.5 (CH),
55.2 (CH), 55.5 (CH3), 70.7 (CH), 76.8 (CH), 78.9 (C), 95.4 (CH2),
129.1, 133.3 (CH), 155.6 (C). IR (ATR): ν ) 2955 (s), 2929 (s),
2857 (m), 1688 (s), 1394 (m), 1365 (m), 1254 (m), 1042 (s). MS
(EI, 230 °C): m/z (%) ) 453 (M+ - Boc, 16), 408 (100), 396
(60), 378 (72), 364 (44), 334 (44), 290 (20, 260 (16). HR-MS
(C26H51NO3Si, M+ - Boc): calcd 453.3638, found 453.3636.
2S,3S,4aR,5R,8aS,5′S-Oct-2-enoic Acid 5-(5-Hydroxyoctyl)-
2-methyldecahydroquinolin-3-yl Ester (1). A 0.013 mL (0.090
mmol) aliquot of 2E-octenoic acid, 0.022 mL (0.136 mmol) of
iPr2NEt, and 0.021 mL (0.136 mmol) of trichlorobenzoylchloride
were dissolved in 1 mL of toluene, and then a solution of 20 mg
(0.045 mmol) of 25 in 1 mL of toluene was added, and the resulting
solution was stirred for 45 min at rt. Afterward a solution of 14
Acknowledgment. We thank Dr. Timm Graening for helpful
discussions during the preparation of this manuscript and Dr.
Elisabeth Irran for calculation of the X-ray structure.
Supporting Information Available: Experimental procedures
for compounds 5, 9, 14-15, 17-22, and 24-25, 1H NMR and 13
C
NMR spectra of all new compounds and the CIF file for compound
3. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO7027079
J. Org. Chem, Vol. 73, No. 8, 2008 3093