Aromatic nucleophilic substitution or CuI-catalyzed coupling route to martinellic acid

Article abstract of DOI:10.1021/jo026125z

Condensation of β-amino ester 8b with triflate 7 gives N-aryl amino ester 11, which is converted into 2-substituted 4-oxoquinoline 4 using an intramolecular Dieckmann reaction as the key step. CuI-mediated coupling of β-amino ester 8a with 1,4-diiodobenzene followed by an intramolecular acylation and Pd-catalyzed carbonylation provide another manner to 4. Alkylation of 4 and subsequent reductive amination deliver the cyclic imine 14, which is transformed into triamine 3 by ordinary operations. Guanylation of 3 under mild condition followed by deprotection results in the synthesis of martinellic acid 1.

Full text of DOI:10.1021/jo026125z

Ar om a tic Nu cleop h ilic Su bstitu tion or Cu I-Ca ta lyzed Cou p lin g
Rou te to Ma r tin ellic Acid
Dawei Ma,* Chengfeng Xia, J iqing J iang, J ianhua Zhang, and Wenjun Tang
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
madw@pub.sioc.ac.cn
Received J uly 1, 2002
Condensation of â-amino ester 8b with triflate 7 gives N-aryl amino ester 11, which is converted
into 2-substituted 4-oxoquinoline 4 using an intramolecular Dieckmann reaction as the key step.
CuI-mediated coupling of â-amino ester 8a with 1,4-diiodobenzene followed by an intramolecular
acylation and Pd-catalyzed carbonylation provide another manner to 4. Alkylation of 4 and
subsequent reductive amination deliver the cyclic imine 14, which is transformed into triamine 3
by ordinary operations. Guanylation of 3 under mild condition followed by deprotection results in
the synthesis of martinellic acid 1.
In tr od u ction
the first total synthesis of martinellic acid. Herein we
wish to detail our efforts on the development of two
routes to the core structure of 1 and 2, as well as the
discovery of a mild reaction condition for guanylation of
hindered secondary amines and its application in the
synthesis of martinellic acid.
Our synthetic strategy for martinellic acid is outlined
in Scheme 1, in which this compound could be synthe-
sized by a guanylation reaction of the tricyclic triamine
3 with a suitable guanylation reagent. The pyrrolidine
ring of 3 could be assembled by alkylation and subse-
quent reductive amination from 2-substituted 4-oxo-
quinoline 4. Two methods would allow us to construct
the skeleton of 4 from enantiopure â-amino ester 8. One
was using an aromatic nucleophilic substitution reaction
of 8 with the triflate 7 to provide the triester 6 and the
subsequent intramolecular Dieckmann reaction. Another
one was through a CuI-catalyzed coupling reaction of 8
with 1,4-diiodobenzene to afford N-aryl â-amino ester 5
and the subsequent intramolecular acylation.
Martinellic acid 1 and martinelline 2 are two alkaloids
that were isolated from an organic extract of Martinella
iquitosensis roots in Merck Research Laboratories.1 Both
compounds contain a pyrroloquinoline ring system, which
had not been discovered in natural products before. More
interestingly, further biological tests revealed that among
these two alkaloids, especially martinelline has potent
antagonist activity to some G-protein coupled receptors
such as bradykinin (BK) B1 and B2, R1-adrenergic, and
muscarinic receptors.1 These are the first examples for
nonpeptide natural products to be identified as BK
receptor antagonists. This character could partially be
used to explain the therapeutic properties of the Marti-
nella as an eye medication in over 13 different ethno-
linguistic groups from eight South American countries.
The unique structure and interesting biological activity
of these compounds have stimulated intense synthetic
studies.2-11 In a previous communication,11 we reported
(1) 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.
Resu lts a n d Discu ssion s
(2) Gurjar, M. K.; Pal, S.; Rao, A. V. R. Heterocycles 1997, 45, 231.
(3) Ho, T. C. T.; J ones, K. Tetrahedron 1997, 53, 8287.
(4) Kim, S. S.; Cheon, H. G.; Kang, S. K.; Yum, E. K.; Choi, J . K.
Heterocycles 1998, 48, 221.
(5) (a) Hadden, M.; Stevenson, P. J . Tetrahedron Lett. 1999, 40,
1215. (b) Hadden, M.; Nieuwenhuyzen, M.; Osborne, D.; Stevenson,
P. J .; Thompson, N.; Tetrahedron Lett. 2001, 42, 6417. (c) Hadden, M.;
Nieuwenhuyzen, M.; Potts, D.; Stevenson, P. J .; Thompson, N.;
Tetrahedron 2001, 57, 5615.
(6) (a) Lovely, C. J .; Mahmud, H. Tetrahedron Lett. 1999, 40, 2079.
(b) Mahmud, H.; Lovely, C. J .; Dias, H. V. R. Tetrahedron 2001, 57,
4095.
(7) (a) Snider, B. B.; Ahn, Y.; Foxman, B. M. Tetrahedron Lett. 1999,
40, 3339. (b) Snider, B. B.; O’Hare, S. M. Tetrahedron Lett. 2001, 42,
2455. (c) Snider, B. B.; Ahn, Y.; O’Hare, S. M. Org. Lett. 2001, 3, 4217.
(8) (a) Batey, R. A.; Simoncic, P. D.; Lin, D.; Smyj, R. P.; Lough, A.
J . Chem. Commun. 1999, 651. (b) Batey, R. A.; Powell, D. A. Chem.
Commun. 2001, 2362.
Syn th esis of 2-Su bstitu ted 4-Oxoqu in olin e 4. The
aromatic nucleophilic substitution protocol for synthesiz-
ing 4 is illustrated in Scheme 2. We started the synthesis
from protected â-amino ester 9,12 which was prepared
from 1,4-butandiol in four steps according to Davies’s
procedure.13 After hydrogenation over Pd/C, free â-amino
ester 8a was obtained. At this time we planned to build
N-aryl â-amino ester 11 via an aromatic nucleophilic
substitution reaction of 8a with the triflate 7, which was
prepared by treating 4-hydroxyisophthalic acid diethyl
ester 10 with trifluoromethanesulfonic anhydride. Al-
though there was no report regarding this kind of
(9) Frank, K. E.; Aube´, J . J . Org. Chem. 2000, 65, 655.
(10) Nieman, J . A.; Ennis, M. D. Org. Lett. 2000, 2, 1395.
(11) Ma, D.; Xia, C.; J iang, J .; Zhang, J . Org. Lett. 2001, 3, 2189.
(12) Ma, D.; Zhang, J . Tetrahedron Lett. 1998, 39, 9067.
(13) Davies, S. G.; Ichihara, O.; Walters, I. A. S. J . Chem. Soc.,
Perkin Trans. 1 1994, 1141.
10.1021/jo026125z CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/28/2002
442
J . Org. Chem. 2003, 68, 442-451

Routes to Martinellic Acid
SCHEME 1
SCHEME 2
SCHEME 3
reaction, the result of Kotsuki and co-workers gave
insight that our idea might work.14 As expected, the
reaction of 8a with 7 under the action of triethylamine
in refluxing acetonitrile provided the coupling product
11. However, the yield was quite low (less than 30%)
mainly because of decomposition of the triflate 7 to the
phenol 10 mediated by the free hydroxy group of 8a .
Therefore, we decided to solve the problem by protecting
the hydroxy group of 8a . Thus, treatment of 8a with tert-
butyldimethylsilyl chloride and triethylamine produced
8b. The coupling reaction of 8b with the triflate 7 in
acetonitrile at 100 °C worked well to afford the substitu-
tion product 11 in 72% yield. Next, triester 11 was
transformed into 4-oxoquinoline 4 by the following four
steps: (1) Dieckmann reaction of 11 in refluxing toluene
under the action of sodium; (2) decarboxylation of the
generated keto ester by hydrolysis with 2 N NaOH,
followed by acidification; (3) esterification of the free acid
with methanolic hydrogen chloride; and (4) reprotection
of the hydroxy group with TBDMS group. The overall
yield was about 30%.
4-oxoquinoline moiety was unstable under the present
reaction conditions. Thus, an alternate route was ex-
plored.
The second method for construction of 4 is demon-
strated in Scheme 3, which relied on a strategy to build
the desired N-aryl â-amino acid skeleton by cuprous ion-
catalyzed coupling of aryl iodide and â-amino ester under
relatively mild condition discovered by our group.15 Thus,
heating of a mixture of the amino ester 8a , 1,4-diiodo-
benzene, CuI, and K2CO3 in DMF at 100 °C for 24 h
provided the N-aryl â-amino acid 5a , which was esterified
with SOCl2/MeOH to afford 5b in 72% overall yield. After
Although the above route to the 2-substituted 4-oxo-
quinoline 4 worked, a drawback was that the Dieckmann
reaction and subsequent decarboxylation steps gave low
yield. This problem might result from the fact that the
(14) Kotsuki, H.; Kobayashi, S.; Suenaga, H.; Nishizawa, Y. Syn-
thesis 1990, 1145.
(15) (a) Ma, D.; Xia, C. Org. Lett. 2001, 3, 2583. (b) Ma, D.; Zhang,
Y.; Yao, J .; Wu, S.; Tao, F. J . Am. Chem. Soc. 1998, 120, 12459.
J . Org. Chem, Vol. 68, No. 2, 2003 443

Ma et al.
SCHEME 4
F IGURE 1. X-ray structure of 16.
SCHEME 5
indirect acylation of the acid 5a under the action of PPA
failed, we decided to run the intramolecular acylation in
a stepwise manner. Thus, protection of both the amino
and hydroxyl groups was the first task. Initially, direct
treatment of the amino acid 5a with acetic anhydride or
acetic chloride was attempted. However, it was observed
that only the O-protection occurred under various condi-
tions. After many experiments, we found if a mixture of
the amino ester 5b and acetic anhydride was heated at
100 °C, the desired N- and O-diprotected product could
be obtained. Hydrolysis of the ester moiety of this
protected product with aqueous NaOH in methanol
followed by reprotection of free hydroxy group with acetyl
anhydride provided the acid 12. Treatment of 12 with
oxalyl chloride produced the corresponding acyl chloride,
which was subjected to an intramolecular acylation
mediated by AlCl3 to afford the ketone 13. Finally, a Pd-
catalyzed carbonylation reaction of aryl iodide 13 followed
by protecting group switch gave 4 in 79% overall yield.
Although this route contained some undesired protection
and deprotection steps due to the failure of direct
acylation of 5a , the stability of the intermediates under
the reaction conditions presented here and the convenient
operation allowed us to synthesize enough 4 for further
conversions.
Syn th esis of th e Tr ia m in e 3. With the intermediate
4 in hand, we tried alkylation and reductive amination
methods16 to set up the pyrrolidine ring of martinellic
acid. The alkylation of 4 was carried out at -40 °C by
using TfOCH2CH2Br as the coupling agent. The gener-
ated bromide was found to be unstable and was therefore
directly converted into the corresponding azide by treat-
ment with sodium azide in DMF. Reduction of this azide
with triphenylphosphine and water produced the free
amine, which attacked spontaneously the ketone moiety
to provide the cyclic imine 14. After the imine 14 was
reduced with sodium borohydride in methanol at -40 °C,
the amine generated was protected with trifluoroace-
tic anhydride to give the amide 15 and its 4-epimer in a
ratio of 2.8/1. Their stereochemistry was established by
NOESY experiment and further confirmed by X-ray
structure analysis of a tetracyclic compound 16, which
was obtained as a side product by deprotection of 15 with
TBAF/HOAc and subsequent cyclization under the as-
sistance of mesyl chloride and triethylamine. The bad
stereoselectivity of the reduction step prompt us to try
other reducing reagents such as L-selectctide and sodium
cyanoborohydride. However, the selectivity was not
improved, although many experiments were performed
(Scheme 4 and Figure 1).
After careful analysis, we felt that if we removed the
silyl group of 14, the free hydroxyl group would probably
chelate with borohydride, thereby eliminating the attack
from the outside and giving better selectivity. Thus,
cleavage of silyl ether in 14 with TBAF/HOAc in THF
provided the alcohol 17. As expected, the reduction of 17
with sodium borohydride followed by protection with
trifluoroacetic anhydride delivered 18 as a sole product
in 94% yield (Scheme 5).
The alcohol 18 was then converted into the azide 19
through its mesylate in 85% overall yield. Reduction of
the azide moiety of 19 with triphenylphosphine and water
followed by deprotection with aqueous hydrochloride in
methanol gave tricyclic triamine 3 as its hydrochloride
salt (Scheme 6).
(16) (a) Sha, C.-K.; Chiu, R.-T.; Yang, C.-F.; Yao, N.-T.; Tseng, W.-
H.; Liao, F.-L.; Wang, S.-L. J . Am. Chem. Soc. 1997, 119, 4130. (b)
Hanessian, S.; Raghavan, S.; Bioorg. Med. Chem. Lett. 1994, 4. 1697.
444 J . Org. Chem., Vol. 68, No. 2, 2003

Routes to Martinellic Acid
SCHEME 6
SCHEME 7
SCHEME 8
Mod el Stu d ies for Gu a n yla tion of th e Ster ica lly
Hin d er ed Secon d a r y Am in e u n d er th e Mild Rea c-
tion Con d ition . Literature survey17 indicated that there
are few reports on the formation of dialkyl guanidine by
guanylation of a sterically hindered secondary amine,17a-c
which implied that introduction of the guanidine moiety
onto the secondary amine of 3 was a challenging task in
the total synthesis of martinellic acid. To solve this
problem several model studies were undertaken. Initially,
we tried to prepare a carbodiimide 22, because this kind
of intermediate was proven to react with hindered
secondary amines easily to afford the corresponding
guanidines.18 Accordingly, treatment of prenylamine with
phenylcarbonyl isothiocyanate in acetonitrile at room
temperature provided the compound 20, which was
deprotected with potassium carbonate in methanol to
give the thiourea 21. Desulfidryzation of 21 with Ph3P/
DIAD (or Ph3P/CCl4/Et3N19) was expected to deliver
carbodiimide 22, which could be trapped with benzyl-
amine to produce guanidine 23.18 However, no desired
product was isolated, mainly because the carbodiimide
22 might be too unstable or even not form under the
present conditions (Scheme 7).
urea 26. The subsequent reaction of 26 with pyrrolidine
worked at 60 °C to afford the N-Boc-protected guanidine
27 in good yield. Unfortunately, when this reagent was
applied to the triamine 3 under the same conditions,
except for adding triethylamine as the HCl trapping
agent, we still did not isolate any guanylation product
(Scheme 8).
In the synthesis of a monosubstituted guanidine by the
reaction of a methylisothiourea intermediate with NH3,
Burgess and co-workers used AgNO3 to promote the
leaving of methanethiol during the guanylation reaction.17i
Stimulated by their report, we did a model study by
reacting 26 with a hindered 2-substituted pyrrolidine 28
under the action of AgNO3. As expected, this reaction
completed at room temperature to produce the displace-
ment product 29 in excellent yield. Fortunately, applica-
tion of this reaction to the triamine 3 worked at 40 °C to
provide the desired coupling product 30 in 20% yield. It
was found that the low yield mainly resulted from the
poor solubility of 3 in acetonitrile. This problem was
solved by using a mixture of acetonitrile and methanol
as the solvent to give improved yield (65%) (Scheme 9).
To demonstrate the usage of the present method to
synthesize N,N,N′-trisubstituted guanidines from the
hindered secondary amines, we did some experiments to
react N-Boc-protected S-methylisothiourea 31 with vari-
ous amines. As shown in Table 1, all hindered secondary
amines were suitable for this reaction to provide the
corresponding displacement product in excellent yield.
This reaction might go through a carbodiimide mecha-
nism that is illustrated in Scheme 10, because the
secondary amine derived N-Boc-protected S-methyl-
isothiourea 41 could not react with benzylamine to
provide guanylation product 42.
Inspired by a report of Flygare and co-workers,17b we
turned our attention to employ methyl isothiourea hy-
droiodide salt 24 as our guanylation agent, which was
prepared by the methylation of the thiourea 21 with
iodomethane. In a model study, reaction of 24 with
pyrrolidine in DMSO at 80 °C under the assistance of
triethylamine gave guanidine 25 in 91% yield. However,
when this reagent was reacted with the triamine 3 under
the same condition, no guanidine formation but decom-
position of the triamine 3 was observed. At this stage
we decided to increase the reactivity of the methyl
isothiourea 24 by introducing an electrodeficient group
on to its nitrogen. Thus, treatment of 24 with di-tert-butyl
dicarbonate assisted by triethylamine gave N-(tert-bu-
toxycarbonyl)-N′-(3-methyl-2-butenyl)-S-methylisothio-
(17) (a) Dodd, D. S.; Wallace, O. B. Tetrahedron Lett. 1998, 39, 5701.
(b) Kearney, P. C.; Fernandez, M.; Flygare, J . A. Tetrahedron Lett.
1998, 39, 2663. (c) Levallet, C.; Lerpiniere, J .; Ko, S. Y. Tetrahedron
1997, 53, 5291. (d) Feichtinger, K.; Zapf, C.; Sings, H. L.; Goodman,
M. J . Org. Chem. 1998, 63, 3804. (e) Barvian, M. R.; Showalter, H. D.
H.; Doherty, A. M. Tetrahedron Lett. 1997, 38, 6799. (f) Yong, Y. F.;
Kowalski, J . A.; Lipton, M. A. J . Org. Chem. 1997, 62, 1540. (g)
Ramadas, K.; Srinivasan, N. Tetrahedron Lett. 1995, 36, 2841. (h)
Drake, B.; Patek, M.; Lebl, M. Synthesis, 1994, 579. (i) Burgess, K.;
Lim, D.; Ho, K. K.; Ke, C. Y. J . Org. Chem. 1994, 59, 2179.
(18) Chinchilla, R.; Na´jera, C.; Sa´nchez-Aullo´, P. Tetrahedron:
Asymmetry, 1994, 5, 1393.
(19) Appel, R.; Kleinstu¨ck, R.; Zehn, K. D. Chem. Ber. 1971, 104,
1335.
J . Org. Chem, Vol. 68, No. 2, 2003 445

Ma et al.
TABLE 1. Gu a n yla tion Rea ction of 31 w ith Va r iou s
SCHEME 9
Am in esa
Syn th esis of Ma r tin ellic Acid . With the compound
30 in hand, we finished the total synthesis of martinellic
acid by the following conversions: (1) hydrolysis of the
ester moiety in 30 with aqueous NaOH in methanol at
reflux and (2) treatment with 5% TFA in methylene
chloride using anisole as a carbocation scavenger20
furnished 1 as its TFA salt. All analytic data of the
synthetic compound were identical with those reported
except for rotation ([R]20 -122.7 (c 0.31, MeOH); lit.1
D
[R]20 -9 (c 0.01, MeOH)) Although the reason for this
D
difference is not clear, one possible explanation is that
either the natural martinellic acid may be partially
racemic or a too dilute solution was used when Merck
chemists measured the rotation (Scheme 11).
In conclusion, we have developed two stereocontrolled
routes for synthesizing the core structure of martinellic
acid and martinelline and a protocol to convert this core
structure to martinellic acid. In addition, the mild
condition presented here for forming protected guanidines
from sterically hindered secondary amine would be of
benefit for preparing the related compounds. Further
conversion of the present intermediate into martinelline
as well as the SAR studies of martinelline analogues are
under investigation in our laboratory.
a
Rea ction con d ition : 31 (1.2 mmol), amine (1 mmol), tri-
ethylamine (2 mmol), and AgNO3 (1.5 mmol) in MeCN (5 mL).
SCHEME 10
Exp er im en ta l Section
Gen er a l P r oced u r es. Analytically pure toluene, DMSO,
and DMF were used directly without further purification. CH2-
Cl2 was distilled from CaH2, and THF was distilled from a deep
blue ketyl prior to use. All other solvents were reagent grade
quality and used as received. Na2SO4 was used as the drying
agent in all workup procedures. Column chromatography was
performed over silica gel (300-400 mesh). All reactions were
run in flame-dried glassware under nitrogen atmosphere
unless stated otherwise.
Eth yl (3S)-Am in o-6-h yd r oxyh exa n oa te 8a . To a solution
of 9 (100 g, 0.22 mol) in 600 mL of ethanol were added
concentrated HCl (22 mL, 0.26 mol), 30 mL of water, and 5 g
of 10% Pd/C. After the reaction mixture was stirred under
hydrogen (50 atm) at 50 °C for 6 h, Pd/C was filtrated off and
the filtrate was neutralized to pH ) 8 with NaHCO3. To this
solution another 5 g of 10% Pd/C was added. The resultant
suspension solution was stirred under the above hydrogenation
conditions for 8 h. After Pd/C was filtered off, the filtrate was
evaporated under reduced pressure to give 38 g of 8a in 98%
1
yield. [R]20 +45.2 (c 0.6, CHCl3); H NMR (300 MHz, CDCl3)
D
dδ 6.65 (m, 2H), 4.15 (q, J ) 7.1 Hz, 2H), 3.59-3.71 (m, 3H),
2.95 (dd, J ) 17.1, 6.8 Hz, 1H), 2.76 (dd, J ) 17.1, 5.9 Hz,
1H), 1.96 (m, 1H), 1.83 (m, 1H), 1.24 (t, J ) 7.1 Hz, 3H); EI-
MS m/z 176 (M+ + H+), 116, 101, 86; HRMS found m/z 175.123
(M+), C8H17NO3 requires 175.121.
(20) Masui, Y.; Chino, N.; Sakakibara, S. Bull. Chem. Soc. J pn. 1980,
53, 464. It was found that complicated products formed without
addition of anisole or with TFA of more than 5% concentration.
446 J . Org. Chem., Vol. 68, No. 2, 2003

Routes to Martinellic Acid
refluxing anhydrous toluene under nitrogen atmosphere was
added a solution of 11 (3.06 g, 6.0 mmol) in 20 mL of anhydrous
toluene in 30 min. The reaction mixture was stirred for 1.5 h
before it was cooled to room temperature. To this solution was
added 5 mL of HOAc with caution to quench the reaction. The
mixture was partitioned between ethyl acetate and water. The
organic layer was separated, washed with water and brine,
dried, and concentrated to give a yellow solid. This crude
product and NaOH (0.72 g, 18 mmol) were dissolved in 20 mL
of water and 60 mL of methanol. The resulting mixture was
stirred at 50 °C for 4 h before 20 mL of HOAc was added at 0
°C. After the mixture was heated at 80 °C for 2 h, the solvent
was removed under reduced pressure and the residue was
dissolved with 50 mL of ethyl acetate. The organic layer was
separated and washed with water and brine, respectively.
After it was dried, the solution was concentrated and the
residue was treated with 60 mL of methanolic hydrogen
chloride overnight at room temperature. The resultant solution
was concentrated and the residue was partitioned between
saturated Na2CO3 and ethyl acetate. The organic layer was
dried and concentrated to give 497 mg of the corresponding
methyl ester.
SCHEME 11
A solution of the above ester (405 mg, 1.54 mmol), imidazole
(200 mg, 2.94 mmol), and TBSCl (300 mg, 2.01 mmol) in 10
mL of anhydrous DMF was stirred at room temperature
overnight. The resultant mixture was partitioned between
ethyl acetate and water. The organic layer was separated,
washed with water and brine, and dried. The solution was
concentrated and the residue was purified by column chro-
matography eluting with 1/6 ethyl acetate/n-hexane to give
Eth yl (3S)-Am in o-6-(ter t-bu tyld im eth ylsila n yoxy)h ex-
a n oa te 8b. To a solution of 8a (11 g, 62.9 mmol) and Et3N
(16 mL, 76 mmol) in 200 mL of anhydrous CH2Cl2 at 0 °C was
added a solution of TBSCl (11.4 g, 75.4 mmol) in 40 mL of
anhydrous CH2Cl2. The reaction mixture was allowed to warm
to room temperature and then stirred overnight. The solution
was diluted with 200 mL of CH2Cl2 and then washed with
water and brine. The organic layer was dried and concentrated.
The residue was purified by column chromatography eluting
with 2/1 ethyl acetate/n-hexane to give 17.5 g (80%) of 8b: 1H
NMR (300 MHz, CDCl3) dδ 4.18 (q, J ) 7.2 Hz, 2H), 3.59 (t, J
) 7.1 Hz, 2H), 3.10 (m, 1H), 2.31 (m, 2H), 1.50-1.11 (m, 7H),
0.85 (s, 9H), 0.00 (s, 6H).
490 mg (30% overall yield) of 4: [R]20 -120.5 (c 1.0, CHCl3);
D
IR (KBr) 3344, 1713, 1666 cm-1; 1H NMR (300 MHz, CDCl3) δ
8.50 (d, J ) 2.1 Hz, 1H), 7.94 (dd, J ) 8.7, 2.1 Hz, 1H), 6.66
(d, J ) 8.7 Hz, 1H), 5.70 (br s, 1H), 3.86 (s, 3H), 3.70 (t, J )
5.3 Hz, 2H), 2.74 (dd, J ) 16.0, 4.1 Hz, 1H), 2.53 (dd, J ) 16.0,
11.6 Hz, 1H), 1.70 (m, 4H), 0.90 (s, 9H), 0.06 (s, 6H); EI-MS
m/z 377 (M+), 346, 320, 246, 228, 204; HRMS found m/z
377.205 (M+), C20H31NO4Si requires 377.202.
Met h yl (3S)-6-H yd r oxyl-3-(4′-iod op h en yla m in o)h ex-
a n oa te 5b. To a solution of amino ester 8a (9.66 g, 45.7 mmol),
1,4-diiodobenze (18.00 g, 54.8 mmol), and potassium carbonate
(18.95 g, 137 mmol) in 100 mL of DMF and 0.5 mL of water
was added CuI (0.87 g, 4.6 mmol). The resultant mixture was
heated at 100 °C under nitrogen atmosphere for 2 days. The
solvent was removed under reduced pressure and the residue
was diluted with 100 mL of CHCl3. After the resultant solution
was acidified to pH ) 5 with 1 N HCl, the organic layer was
separated and the aqueous layer was extracted with CHCl3
in three portions. The combined organic layers were washed
with brine, dried, and concentrated to dryness to give the crude
amino acid 5a .
4-(Tr iflu or om eth a n esu lfon yloxy)isop h th a lic Acid Di-
eth yl Ester 7. To a solution of 10 (10.82 g, 45.5 mmol) and
Et3N (12.7 g, 90.6 mmol) in 100 mL of anhydrous CH2Cl2 at
-15 °C was added a solution of Tf2O (9.18 mL, 54.5 mmol) in
15 mL of CH2Cl2. The reaction mixture was stirred for 0.5 h
before 100 mL of CH2Cl2 was added. The resultant solution
was washed with 20 mL of saturated NaHCO3 and 20 mL of
brine. The organic layer was dried and concentrated. The
residue was purified by column chromatography eluting with
1/5 ethyl acetate/n-hexane to give 13 g (77%) of 7. 1H NMR
(300 MHz, CDCl3) δ 8.72 (d, J ) 2.2 Hz, 1H), 8.28 (dd, J )
8.7, 2.1 Hz, 1H), 7.38 (d, J ) 8.6 Hz, 1H), 4.45 (m, 4H), 1.42
(m, 6H).
To a solution of the above crude acid in 200 mL of methanol
was added SOCl2 (4.75 mL, 55 mmol) in a dropwise manner
at 0 °C. The mixture was stirred overnight at room temper-
ature. After the methanol was evaporated, 50 mL of saturated
NaHCO3 was employed to neutralize the residue. The result-
ant mixture was extracted with ethyl acetate in three portions.
The combined organic layers were washed with brine, dried,
and concentrated. The residue was purified by column chro-
matography eluting with 1/1 ethyl acetate/petroleum ether to
(2′S)-4-[5′-(ter t-Bu tyld im eth ylsila n yloxy)-1′-eth oxyca r -
bon ylp en t-2′-yl]a m in oisop h th a lic Acid Dieth yl Ester 11.
A solution of 7 (3.50 g, 9.45 mmol), 8b (2.78 g, 9.62 mmol),
and Et3N (1.6 mL, 11.4 mmol) in 4 mL of anhydrous MeCN
was heated at 100 °C in
a sealed tube under nitrogen
atmosphere for 12 h. The cooled solution was diluted with 100
mL of ethyl acetate before it was washed with water and brine.
The organic layer was dried and concentrated. The residue was
purified by column chromatography eluting with 1/8 ethyl
acetate/n-hexane to give 3.49 g (72%) of 11: [R]20D +4.2 (c 0.6,
afford 11.9 g (72% yield for two steps) of 5b: [R]20 -20.4 (c
D
1.0, CHCl3); IR (KBr) 3388, 1727, 1590 cm-1
;
1H NMR (300
1
CHCl3); IR (KBr) 1763, 1712, 1686 cm-1; H NMR (300 MHz,
MHz, CDCl3) δ 7.40 (d, J ) 7.0 Hz, 2H), 6.41 (d, J ) 7.0 Hz,
2H), 3.72 (m, 1H), 3.64 (s, 3H), 2.50 (m, 2H), 1.75-1.59 (m,
4H); EI-MS m/z 363 (M+), 304, 290, 237, 178, 104; HRMS calcd
for C13H18INO3 (M+) 363.0331, found 363.0323.
(3S)-6-Acetoxy-3-[N-(4′-iod op h en yl)a ceta m id o]h exa n o-
ic Acid 12. A solution of 5b (15.5 g, 42.7 mmol) in 200 mL of
acetic anhydride was heated to 100 °C for 2 h. The solvent
was evaporated under reduced pressure. The residue was
purified by column chromatography eluting with 2/1 petroleum
ether/ethyl acetate to give 17.5 g of the corresponding amide.
CDCl3) δ 8.63 (d, J ) 2.1 Hz, 1H), 8.39 (br s, 1H), 7.97 (dd, J
) 9.1, 2.1 Hz, 1H), 6.79 (d, J ) 9.1 Hz, 1H), 4.35 (dd, J )
14.2, 7.1 Hz, 4H), 4.13 (m, 2H), 4.08 (m, 1H), 3.62 (t, J ) 6.1
Hz, 2H), 2.60 (m, 2H), 1.70 (m, 4H), 1.40 (m, 6H), 1.23 (t, J )
7.0 Hz, 3H), 0.91 (s, 9H), 0.30 (s, 6H); EI-MS m/z 509 (M+),
464, 422, 364, 290, 318; HRMS found m/z 509.281 (M+); C26H43
-
NO7Si requires 509.281.
(2S)-2-(3-ter t-Bu tyldim eth ylsilyloxypr opyl)-4-oxo-1,2,3,4-
tetr a h yd r oqu in olin e-6-ca r boxylic Acid Meth yl Ester 4.
To a suspension of Na (700 mg, 30.4 mmol) in 80 mL of
J . Org. Chem, Vol. 68, No. 2, 2003 447

Ma et al.
To a solution of the above amide (17.5 g, 39.1 mmol) in 200
mL of MeOH and 100 mL of water was added NaOH (6.4 g,
160 mmol). After the mixture was stirred for 20 h, the reaction
was quenched by adding concentrated HCl. The MeOH was
removed under reduced pressure and the aqueous layer was
extracted with CHCl3 three times. The combined organic layers
were dried and concentrated. The residue was purified by
column chromatography eluting with 1/1 ethyl acetate/
petroleum ether (containing 2% acetic acid) to give 14.7 g of
alcohol.
of tert-butyldimethylsilyl chloride (1.64 g, 10.9 mmol) in 2 mL
of CH2Cl2. The reaction mixture was stirred at room temper-
ature for 6 h and then diluted with 30 mL of water. After the
aqueous phase was extracted with CH2Cl2, the combined
extracts were washed with brine and dried. Purification of the
residue by flash column chromatography eluting with 1/6 ethyl
acetate/n-hexane gave 3.6 g of 4 (79% yield for three steps) as
a straw-yellow solid: [R]20 -120.5 (c 1.0, CHCl3); IR (KBr)
D
1
3344, 1713, 1666 cm-1; H NMR (300 MHz, CDCl3) δ 8.50 (d,
J ) 2.1 Hz, 1H), 7.93 (dd, J ) 8.7, 2.1 Hz, 1H), 6.64 (d, J )
8.7 Hz, 1H), 5.19 (br s, 1H), 3.87 (s, 3H), 3.69 (t, J ) 5.3 Hz,
2H), 2.73 (dd, J ) 16.1, 4.1 Hz, 1H), 2.53 (dd, J ) 16.1, 11.6
Hz, 1H), 1.26-1.75 (m, 4H), 0.92 (s, 9H), 0.08 (s, 6H); EI-MS
m/z 377 (M+), 346, 320, 246, 228, 204; HRMS found m/z
377.2049 (M+), C20H31NO4Si requires 377.2022.
The above alcohol (14.7 g, 37.6 mmol) was dissolved in 150
mL of Ac2O before it was heated with stirring at 80 °C for 2 h.
After the solution was concentrated in vacuo, the residue was
dissolved in 100 mL of 1,4-dioxane and 50 mL of water and
stirred at 50 °C for 0.5 h. The solvent was evaporated under
reduced pressure and the residue was diluted with 150 mL of
CHCl3. The resultant solution was washed with brine, dried,
and concentrated. The residue was purified by column chro-
matography eluting with 2/1 ethyl acetate/n-hexane to give
(3aS,4S)-4-(3-ter t-Bu tyldim eth ylsilyloxypr opyl)-3,3a,4,5-
tetr a h yd r o-2H-p yr r olo[3,2-c]qu in olin e-8-ca r boxylic Acid
Meth yl Ester 14. To a solution of 4 (1.0 g, 2.65 mmol) in 2.5
mL of anhydrous THF at -78 °C was slowly added a 1.0 M
solution of lithium hexamethyldisilazide (5.6 mL, 5.6 mmol)
in THF. The reaction mixture was allowed to warm to -40 °C
over a 0.5 h period, and then treated with BrCH2CH2OTf (1.59
g, 5.83 mmol) at -40 °C. The mixture was stirred for 1 h at
this temperature, quenched with saturated NH4Cl, and diluted
with EtOAc. The aqueous layer was separated and extracted
with EtOAc. The combined organic layers were washed with
brine, dried, and concentrated in vacuo. Purification of the
residue by column chromatography eluting with 1/8 ethyl
acetate/n-hexane produced crude alkylation product.
To a solution of the above crude product in 10 mL of DMF
was added sodium azide (345 mg, 5.3 mmol). This slurry was
stirred for 10 h under nitrogen atmosphere before the solvent
was evaporated in vacuo. After 5 mL of water was added to
dissolve the residue, extraction with ethyl acetate was carried
out. The combined extracts were dried over Na2SO4 and
concentrated in vacuo to provide the corresponding azide.
15.5 g (84% yield for three steps) of 12: [R]20 -3.7 (c 0.84,
D
1
CHCl3); IR (KBr) 3445, 1727, 1633 cm-1; H NMR (300 MHz,
CDCl3) δ 7.99 (d, J ) 8.5 Hz, 2H), 7.00 (br s, 2H), 5.22 (m,
1H), 4.06 (t, J ) 6.4 Hz, 2H), 3.39 (br s, 1H), 2.43 (d, J ) 6.6
Hz, 2H), 2.05 (s, 3H), 1.79 (s, 3H), 1.77-1.72 (m, 2H), 1.57-
1.45 (m, 2H); EI-MS m/z 433 (M+), 391, 331, 290, 261, 245,
219.
(2S)-2-(3-Acetoxyp r op yl)-1-a cetyl-6-iod o-4-oxo-1,2,3,4-
tetr a h yd r oqu in olin e 13. To an ice-cooled suspension of 12
(10.0 g, 23 mmol) and 0.05 mL of DMF in 100 mL of dry CH2-
Cl2 was added oxalyl chloride (3 mL, 34.6 mmol) in 10 min.
The mixture was stirred for another 10 min at 0 °C and then
1 h at room temperature. After the solvent was evaporated to
dryness, another 100 mL of dry CH2Cl2 was added. To this
stirring solution was added AlCl3 (9.8 g, 73.6 mmol) in several
portions at 0 °C. The resultant reaction mixture was stirred
for 12 h at room temperature and then cautiously quenched
into a rapidly stirred mixture of 200 g of ice and 100 mL of
CHCl3. The organic layer was separated and the aqueous layer
was extracted with CHCl3. The combined organic layers were
washed with brine, dried, and concentrated. The residue was
purified by column chromatography eluting with 1/2 ethyl
acetate/n-hexane to give 5.9 g (62%) of 13. [R]20D +203.0 (c 1.1,
A solution of the above azide, PPh3 (0.94 g, 3.6 mmol), and
water (0.2 mL) in 10 mL of THF was stirred at ambient
temperature for 14 h. The reaction mixture was concentrated
to dryness under reduced pressure. The residue was purified
by column chromatography eluting with 1/8 ethyl acetate/n-
hexane to produce 512 mg (48% yield for three steps) of 14:
1
CHCl3); IR (KBr) 3448, 1736, 1664 cm-1; H NMR (300 MHz,
[R]20 -68.9 (c 0.50, CHCl3); IR (KBr) 3231, 1702 cm-1 1H
;
D
CDCl3) δ 8.31 (d, J ) 1.9 Hz, 1H), 7.86 (dd, J ) 8.5, 1.9 Hz,
1H), 7.10 (br s, 1H), 5.18 (br s, 1H), 3.97 (t, J ) 5.5 Hz, 2H),
3.01 (dd, J ) 18.1, 5.8 Hz, 1H), 2.65 (d, J ) 18.0 Hz, 1H), 2.33
(s, 3H), 1.96 (s, 3H), 1.76-1.54 (m, 4H); EIMS m/z 415 (M+),
373, 272; HRMS found m/z 415.0298 (M+), C16H18INO4 requires
415.0281.
NMR (300 MHz, CDCl3) δ 8.56 (d, J ) 1.8 Hz, 1H), 7.86 (dd,
J ) 8.7, 2.0 Hz, 1H), 6.60 (d, J ) 8.4 Hz, 1H), 4.90 (br s, 1H),
4.19 (m, 1H), 3.93 (s, 3H), 3.82 (m, 1H), 3.76 (m, 2H), 3.20 (m,
1H), 2.81 (m, 1H), 2.27 (m, 1H), 1.82 (m, 1H), 1.74-1.62 (m,
4H); EI-MS m/z 402 (M+), 345, 269, 242, 229; HRMS found m/
z 402.2311 (M+), C22H34N2O3Si requires 402.2339.
An Alter n a tive Rou te to 4. To a solution of 13 (5 g, 12
mmol) in 50 mL of DMF and 2 mL of MeOH were added Et3N
(3.3 mL, 24 mmol), dppp (247 mg, 0.6 mmol), and Pd(OAc)2
(135 mg, 0.6 mmol). The resulting suspension was purged with
CO and stirred at 80 °C in a CO atmosphere (balloon pressure).
After 12 h of stirring, the DMF was evaporated in vacuo and
100 mL of CHCl3 was added to dissolve the residue. The
solution was washed with water, dried, and concentrated in
vacuo. The residue was purified by flash column chromatog-
raphy eluting with 1/2 ethyl acetate/petroleum ether to give
3.86 g of the corresponding methyl ester.
The above methyl ester (3.86 g, 11.1 mmol) was dissolved
in 30 mL of methanolic hydrogen chloride and 3 mL of water.
The reaction mixture was stirred overnight at room temper-
ature. The solvent was removed under reduced pressure, and
the residue was neutralized by saturated NaHCO3 and then
extracted with CHCl3. The combined organic layers were dried
and concentrated in vacuo. Purification of the residue by
column chromatography eluting with ethyl acetate gave 2.60
g of the amino alcohol.
(1a S,3a S,4S)-2-(3-ter t-Bu t yld im et h ylsilyloxyp r op yl)-
1,5-bis(tr iflu or oa cetyl)-2,3,3a ,4,5,9b-h exa h yd r o-1H-p yr -
r olo[3,2-c]qu in olin e-8-ca r boxylic Acid Meth yl Ester 15.
A solution of 14 (232 mg, 0.58 mmol) in 5 mL of MeOH at
-40 °C was treated with NaBH4 (87 mg, 2.3 mmol). The
reaction mixture was allowed to warm to room temperature
for a 2 h period. The solvent was removed under reduced
pressure before 5 mL of water was added to dissolve the
residue and then extracted with CHCl3. The extracts were
dried and concentrated to dryness. The residue, Et3N (0.28 mL,
2.03 mmol), and a catalytic amount of DMAP were dissolved
in 5 mL of anhydrous CH2Cl2. To this stirring solution was
added a solution of (CF3CO)2O (0.25 mL, 1.74 mmol) in 1 mL
of CH2Cl2. After the reaction mixture was stirred for 2 h at
room temperature, it was diluted with 10 mL of CH2Cl2 and
10 mL of water. The organic layer was separated and the
aqueous layer was extracted with CH2Cl2. The combined
organic extracts were dried and concentrated to dryness. The
residue was purified by column chromatography eluting with
1/8 ethyl acetate/petroleum ether to give 245 mg of 15 as a
colorless oil and 89 mg of its 4-epimer. 15: [R]20D +19.5 (c 0.74,
To a solution of the above amino alcohol (2.6 g, 9.9 mmol),
Et3N (1.93 mL, 13.8 mmol), and a catalytic amount of DMAP
in 30 mL of CH2Cl2 at room temperature was added a solution
1
CHCl3); IR (KBr) 1726, 1692, 1440 cm-1; H NMR (300 MHz,
CDCl3) δ 8.46 (d, J ) 1.4 Hz, 1H), 8.05 (dd, J ) 8.3, 1.5 Hz,
448 J . Org. Chem., Vol. 68, No. 2, 2003

Routes to Martinellic Acid
1H), 7.43 (br s, 1H), 5.39 (br s, 1H), 4.72 (br s, 1H), 3.95 (s,
3H), 3.53 (m, 2H), 2.74 (m, 1H), 2.33 (m, 1H), 2.13 (m, 1H),
1.64-1.41 (m, 6H), 0.83 (s, 9H), 0.02 (s, 6H); ESI-MS m/z 1216
(2M+ + Na+), 597 (M+ + H+), 565 (M+ - OMe); EI-MS m/z 581
(M+ - Me), 518, 450, 423, 395; HRMS found m/z 581.1918 (M+
mmol) via syringe and the reaction mixture was stirred for 1
h at room temperature. The reaction mixture was partitioned
between CH2Cl2 and water. The organic layer was separated
and the aqueous layer was extracted with CH2Cl2. The
combined organic layers were dried and concentrated. The
residue was purified by column chromatography eluting with
3/2 ethyl acetate/n-hexane to produce 185 mg of the corre-
sponding mesylate.
- Me), C25H31F6N2O5Si requires 581.1907. 4-Epimer of 15:
1
[R]20 +310.3 (c 0.59, CHCl3); IR (KBr) 1698, 1618 cm-1; H
D
NMR (300 MHz, CDCl3) δ 8.02 (dd, J ) 8.3, 1.9 Hz, 1H), 7.62
(s, 1H), 7.35 (d, J ) 8.1 Hz), 4.58 (m, 1H), 4.37 (d, J ) 11.8
Hz, 1H), 4.24 (t, J ) 9.2 Hz, 1H), 3.93 (s, 3H), 3.77 (m, 1H),
3.61 (m, 2H), 2.25 (m, 1H), 1.97 (m, 1H), 1.80-1.71 (m, 3H),
1.56-1.48 (m, 2H), 0.86 (s, 9H), 0.02 (s, 6H); ESI m/z 1216
(2M+ + Na+), 597 (M+ + H+), 565 (M+ - OMe); EI-MS m/z
581 (M+ - Me), 518, 450, 423, 395; HRMS found m/z 596.2150
(M+), C26H34F6N2O5Si requires 596.2141.
To a solution of the above mesylate (164 mg, 0.30 mmol) in
5 mL of DMF was added sodium azide (60 mg, 0.90 mmol).
This slurry was stirred for 10 h under nitrogen atmosphere
before the solvent was evaporated in vacuo. The residue was
partitioned between ethyl acetate and water. The organic layer
was separated and the aqueous layer was extracted with ethyl
acetate. The combined extracts were dried and concentrated
to dryness. The residue was purified by column chromatog-
raphy eluting with 1/1 ethyl acetate/n-hexane to give 134 mg
(88%) of 19: [R]20D +41.0 (c 0.95, CHCl3); IR (KBr) 2101, 1725,
(1a S,3a S,4S)-1-Tr iflu or oa cet yl-2,3,3a ,3b ,4,5,6,11b -oc-
ta h yd r o-1H-d ip yr r olo[1,2-a ,3′,2′-c]qu in olin e-10-ca r boxy-
lic Acid Meth yl Ester 16. To a solution of 15 (14 mg, 0.023
mmol) in 1 mL of THF were added TBAF (12 mg, 0.046 mmol)
and HOAc (2 µL). The mixture was stirred for 2 h and then
partitioned between CH2Cl2 and water. The aqueous phase was
extracted with CH2Cl2. The combined organic layers were dried
and concentrated to dryness. The residue, Et3N (7 µL, 0.05
mmol), and a catalytic amount of DMAP were dissolved in 1
mL of CH2Cl2. After MsCl (3 µL, 0.039 mmol) was added by
syringe, the reaction mixture was stirred for 1 h at room
temperature. The reaction mixture was partitioned between
CH2Cl2 and water. The organic layer was separated and the
aqueous layer was extracted with CH2Cl2. The combined
organic layers were dried and concentrated to dryness. The
residue was purified by column chromatography eluting with
1
1693 cm-1; H NMR (300 MHz, CDCl3) δ 8.45 (d, J ) 1.6 Hz,
1H), 8.06 (dd, J ) 8.4, 1.7 Hz, 1H), 7.33 (br s, 1H), 5.34 (br s,
1H), 4.73 (br s, 1H), 3.91 (s, 3H), 3.56 (m, 1H), 3.24 (t, J ) 5.9
Hz, 2H), 2.68 (m, 1H), 2.33 (m, 1H), 2.13 (m, 1H), 1.69-1.47
(m, 5H); EI-MS m/z 507 (M+), 476, 382, 365; HRMS found m/z
507.1342 (M+), C20H19F6N2SO7 requires 507.1341.
(1aS,3aS,4S)-4-(3-Am in opr opyl)-2,3,3a,4,5,9b-h exah ydr o-
1H-p yr r olo[3,2-c]qu in olin e-8-ca r boxylic Acid Meth yl Es-
ter 3. A solution of 19 (134 mg, 0.26 mmol), PPh3 (208 mg,
0.79 mmol), and water (0.1 mL) in 2 mL of THF was stirred
at ambient temperature for 14 h. The reaction mixture was
concentrated to dryness under reduced pressure. The residue
was treated with 5 mL of methanolic hydrogen chloride and 1
mL of water overnight. The solvent was removed under
reduced pressure and 5 mL of water was added to dissolve
the residue. The aqueous phase was extracted with EtOAc
twice. The organic extracts were discarded, and the aqueous
layer was concentrated to dryness in vacuo to produce 76 mg
of 3 in 81% yield as its hydrochloride salt: [R]20D -49.9 (c 1.25,
CH3OH); IR (KBr) 3420, 1618, 1509 cm-1; 1H NMR (300 MHz,
CD3OD) δ 8.03 (d, 1.5 Hz, 1H), 7.76 (dd, J ) 8.6, 1. 3 Hz, 1H),
6.88 (d, J ) 8.7 Hz, 1H), 4.69 (d, J ) 3.8 Hz, 1H), 3.84 (s, 3H),
3.41 (m, 2H), 3.13 (m, 1H), 3.04 (m, 2H), 2.45 (m, 2H), 2.18
1/2 ethyl acetate/n-hexane to produce 7 mg (83%) of 16: [R]20
D
-29.4 (c 0.94, CHCl3); IR (KBr) 1705, 1685, 1604 cm-1 1H
;
NMR (300 MHz, CDCl3) δ 8.55 (s, 1H), 7.86 (d, J ) 8.6 Hz,
1H), 6.49 (d, J ) 8.6 Hz, 1H), 5.06 (d, J ) 5.5 Hz, 1H), 3.89
(m, 1H), 3.84 (s, 3H), 3.64 (m, 1H), 3.45 (m, 2H), 3.01 (m, 1H),
2.29 (m, 1H), 2.21-2.10 (m, 2H), 1.97 (m, 2H), 1.63 (m, 2H).
EI-MS m/z 368 (M+), 339, 308, 271, 228; HRMS found m/z
368.1334 (M+), C18H19F3N2O3 requires 368.1348.
(1a S ,3a S ,4S )-4-(3-H yd r oxyp r op yl)-1,5-b is(t r iflu or o-
a cetyl)-2,3,3a ,4,5,9b-h exa h yd r o-1H-p yr r olo[3,2-c]qu in o-
lin e-8-ca r boxylic Acid Meth yl Ester 18. A solution of 14
(300 mg, 0.70 mmol) in 10 mL of THF was treated with TBAF
(275 mg, 1.05 mmol) and HOAc (90 µL, 1.6 mmol) for 6 h. After
30 mL of ethyl acetate was added to dilute the reaction
mixture, it was washed with water and brine. The organic
layer was dried and concentrated. The residue was dissolved
in 10 mL of THF and 0.5 mL of HOAc before NaBH4 (79 mg,
2.1 mmol) was added at 0 °C. The suspension was stirred for
4 h. The solvent was removed under reduced pressure and the
residue was dissolved with 20 mL of CHCl3. The organic layer
was washed with water and brine, dried, and concentrated.
The residue was dissolved in 10 mL of anhydrous CH2Cl2, and
then Et3N (0.49 mL, 3.5 mmol), a catalytic amount of DMAP,
and (CF3CO)2O (0.35 mL, 2.45 mmol) were added. After the
resulting mixture was stirred at room temperature overnight,
20 mL of CH2Cl2 was added to dilute the reaction mixture.
The organic layer was washed with water and brine, dried,
and concentrated. The residue was purified by column chro-
matography eluting with 2/1 ethyl acetate/n-hexane to give
317 mg of 18 in 94% yield for three steps: [R]20D +65.1 (c 0.97,
(m, 1H), 1.92-1.74 (m, 4H); EI-MS m/z 289 (M+), 259 (M+
CH2NH2), 245, 228, 214; HRMS found m/z 259.1437 (M+
CH2NH2), C15H19N2O2 requires 259.1447.
-
-
1-Ben zoyl-3-(3′-m eth ylbu t-2′-en yl)th iou r ea 20. To a sus-
pension of KSCN (6.16 g, 63.4 mmol) in 50 mL of anhydrous
acetone was added slowly benzoyl chloride (7.36 mL, 63.4
mmol). After the mixture was stirred at room temperature for
1 h, the resultant precipitant was filtered off and the filtrate
was concentrated to dryness. The residue was dissolved with
50 mL of anhydrous MeCN and then a solution of 3-methylbut-
2-enylamine (5.4 g, 63.4 mmol) in 10 mL of anhydrous MeCN
was added. The resultant solution was stirred overnight before
the solvent was removed under reduced pressure. The residue
was purified by column chromatography eluting with 2/1 ethyl
acetate/n-hexane to give 10.7 g (68%) of 20: IR (KBr) 3222,
1665, 1535 cm-1 1H NMR (300 MHz, CDCl3) δ 10.57 (br s,
;
1H), 9.00 (br s, 1H), 7.85-7.82 (m, 2H), 7.44-7.49 (m, 3H),
5.36 (t, J ) 8.1 Hz, 1H), 4.27 (m, 2H), 1.78 (s, 3H), 1.74 (s,
3H); EI-MS m/z 248 (M+), 234, 213, 205, 122, 105, 84, 77;
HRMS found m/z 248.1022 (M+), C13H16N2OS requires 248.0983.
1
CHCl3); IR (KBr) 3126, 1691, 1613 cm-1; H NMR (300 MHz,
1-(ter t-Bu toxyca r bon yl)-3-(3′-m eth ylbu t-2′-en yl)-2-m e-
th ylisoth iou r ea 26. To a solution of 20 (6.04 g, 24.3 mmol)
in 20 mL of methanol was added K2CO3 (6.36 g, 46 mmol) and
the resulting mixture was stirred at room temperature for 6
h. The solvent was removed in vacuo and then 50 mL of CHCl3
was added to dissolve the residue. The resultant solution was
washed with water and brine and dried. After removal of the
solvent, the residue was chromatographed eluting with 30/1
chloroform/methanol to give 3.3 g of 21 in 94% yield: IR (KBr)
CDCl3) δ 8.47 (s, 1H), 8.04 (d, J ) 7.7 Hz, 1H), 7.41 (br s, 1H),
5.38 (br s, 1H), 4.78 (br s, 1H), 3.96 (s, 3H), 3.62 (m, 2H), 2.76
(m, 1H), 2.36 (m, 1H), 2.16 (m, 1H), 1.74 (m, 2H), 1.47 (m,
4H); EIMS m/z 482 (M+), 450, 423, 395, 284; HRMS found m/z
482.1267 (M+), C20H20F6N2O5 requires 482.1277.
(1a S,3a S,4S)-4-(3-Azid op r op yl)-1,5-bis(tr iflu or oa cetyl)-
2,3,3a,4,5,9b-h exah ydr o-1H-pyr r olo[3,2-c]qu in olin e-8-car -
boxylic Acid Meth yl Ester 19. A solution of 18 (164 mg, 0.35
mmol), Et3N (78 µL, 0.56 mmol), and a catalytic amount of
DMAP in 5 mL of CH2Cl2 was treated with MsCl (36 µL, 0.46
3426, 3235, 3184, 1627 cm-1 1H NMR (300 MHz, CDCl3) δ
;
6.49 (br s, 1H), 5.96 (br s, 2H), 5.24 (t, J ) 6.5 Hz, 1H), 3.76
J . Org. Chem, Vol. 68, No. 2, 2003 449

Ma et al.
(m, 2H), 1.76 (s, 3H), 1.70 (s, 3H); EI-MS m/z 144 (M+), 129,
120, 111, 101, 68, 41; HRMS found m/z 144.0721 (M+),
C6H12N2S requires 144.0721.
A solution of 21 (3.3 g, 22.9 mmol) and CH3I (2.85 mL, 45.8
mmol) in 20 mL of anhydrous DMF was stirred at room
temperature overnight. The solvent was removed in vacuo to
give 6 g of a crude of 24.
anhydrous trifluoroacetic acid were added. The mixture was
stirred at room temperature for 14 h and then concentrated.
The residue was purified by reversed phase column chroma-
tography (C18 silica gel) eluting with 8/1 to 2/1 water/methanol
to give 15 mg of 1 in 65% yield as its trifluoroacetic salt: [R]20
D
-122.7 (c 0.31, MeOH); 1H NMR (400 MHz, CDCl3) δ 7.65 (s,
1H), 7.55 (d, J ) 8.5 Hz, 1H), 6.59 (d, J ) 8.5 Hz, 1H), 5.34 (t,
J ) 6.6 Hz, 1H), 5.31 (d, J ) 6.5 Hz, 1H), 5.18 (t, J ) 6.8 Hz,
1H), 3.97 (dd, J ) 15.3, 6.5 Hz, 1H), 3.87 (dd, J ) 15.3, 6.3
Hz, 1H), 3.74 (d, J ) 6.6 Hz, 2H), 3.39 (m, 2H), 3.28(m, 1H),
3.14 (m, 2H), 2.45 (m, 1H), 2.08(m, 1H), 1.74 (s, 3H), 1.70 (s,
3H), 1.69 (s, 3H), 1.64 (s, 3H),1.69-1.63 (m, 2H), 1.56-1.45
(m, 3H); 13C NMR (400 MHz, CDCl3) δ 167.2, 155.5, 154.3,
146.4, 136.1, 135.7, 130.5, 130.1, 119.6, 119.2, 117.1, 115.8,
113.3, 53.1, 49.1, 45.7, 40.7, 39.7, 39.2, 38.8, 33.4, 26.3, 25.5,
25.4, 25.2, 18.0, 17.9; ESI-MS m/z 724 (M+ + H+ + 2CF3-
COOH), 610 (M+ + H+ + CF3COOH), 496 (M+ + H+), 428.
3-Ben zyl-1-(ter t-b u t yloxyca r b on yl)-2-m et h ylisot h io-
u r ea 31. Following the procedure for synthesizing 26 from
3-methyl-but-2-enylamine, compound 31 was prepared from
To a solution of above crude product, Et3N (6.73 mL, 48.3
mmol), and catalytic DMAP in 20 mL of anhydrous CH2Cl2
was added (Boc)2O (5.52 g, 25.3 mmol). After the mixture was
stirred at room temperature for 4 h, it was washed by water
and brine. The organic layer was dried and concentrated. The
residue was purified by column chromatography eluting with
30/1 chloroform/methanol to give 5.27 g of 26 in 89% yield for
two steps: IR (KBr) 3244, 1637 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 9.64 (br s, 1H), 5.23 (t, J ) 7.0 Hz, 1H), 3.88 (m,
2H), 2.47 (s, 3H), 1.74 (s, 3H), 1.68 (s, 3H), 1.50 (s, 9H); EI-
MS m/z 259 (M+ + H+), 203, 185, 169, 159, 137, 117, 69, 57,
41; HRMS found m/z 258.1429 (M+), C12H22N2SO2 requires
258.1402.
benzylamine in 89% yield: IR (KBr) 3238, 1721, 1647 cm-1
;
(2′S)-N1-Ben zyl-N2-(ter t-bu toxyca r bon yl)-1′-[2′-(d ip h e-
n ylm eth yl)p yr r olid in e]ca r boxa m id in e 29. To a solution
of 26 (23 mg, 0.089 mmol), 28 (23 mg, 0.097 mmol), and Et3N
(14 µL, 0.10 mmol) in 2 mL of anhydrous MeCN was added a
solution of AgNO3 (16 mg, 0.094 mmol) in 0.5 mL of MeCN in
30 min. After the mixture was stirred overnight in the dark,
the resultant precipitate was filtered off and the filtrate was
concentrated to dryness. The residue was dissolved in 10 mL
of CHCl3 and then washed with water and brine. The organic
layer was dried and concentrated. The residue was purified
by column chromatography eluting with 20/1 chloroform/
methanol to give 33 mg (84%) of 29: IR (KBr) 3275, 1633, 1581
1H NMR (300 MHz, CDCl3) δ 10.2 (br s, 1H), 7.35 (m, 5H),
4.52 (d, J ) 5.7 Hz, 2H), 2.48 (s, 3H), 1.51 (s, 9H); EI-MS m/z
280 (M+), 252, 224, 209, 158, 91; HRMS found m/z 280.1216
(M+), C14H20N2O2S requires 280.1246.
Gen er a l P r oced u r e of AgNO3-P r om oted Gu a n yla tion
fr om 31. To a solution of compound 31 (1.0 mmol), amine (1.0
mmol), and Et3N (2.0 mmol) in 5 mL of anhydrous MeCN was
added a solution of AgNO3 (1.5 mmol) in 1 mL of MeCN over
30 min. After the mixture was stirred for 4 h in the dark, the
resultant precipitate was filtered and the filtrate was concen-
trated to dryness. The residue was dissolved by 10 mL of
CHCl3 and then washed with water and brine. After the
solution was dried and concentrated, the residue was purified
by column chromatography eluting with 10/1 to 30/1 chloroform/
methanol to give the corresponding guanylation product.
N1-Ben zyl-N2-(ter t-bu toxyca r bon yl)-4′-m or p h olin eca r -
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.33-7.14 (m, 10H), 5.31
(m, 1H), 5.03 (t, J ) 8.1 Hz, 1H), 4.16 (d, J ) 8.4 Hz, 2H),
3.60 (m, 1H), 3.37 (m, 2H), 2.08 (m, 2H), 1.77 (m, 2H), 1.61 (s,
3H), 1.54 (s, 3H), 1.47 (s, 9H); EI-MS m/z 447 (M+), 390, 373,
346, 236, 224, 206, 165, 138, 70; HRMS found m/z 447.2894
(M+), C28H37N3O2 requires 447.2886.
boxa n id in e 32: 99% yield; IR (KBr) 3183, 3090, 1662 cm-1
;
1H NMR (300 MHz, CDCl3) δ 8.9 (br s, 1H), 7.30 (m, 5H), 4.39
(s, 2H), 3.69 (d, J ) 4.8 Hz, 4H), 3.39 (d, J ) 4.9 Hz, 4H), 1.50
(s, 9H); EI-MS m/z 319 (M+), 264, 247, 219, 188, 158, 133, 106,
91; HRMS found m/z 264.1356 (M+ - But + H+), C13H18N3O3
requires 264.1348.
Com p ou n d 30. To a solution of 3 (62 mg, 0.16 mmol), 26
(200 mg, 0.78 mmol), and Et3N (0.26 mL, 1.87 mmol) in MeCN
(2 mL) and MeOH (1 mL) was added dropwise a solution of
AgNO3 (185 mg, 1.09 mmol) in 0.5 mL of MeCN over a 0.5 h
period. After the reaction mixture was stirred overnight in the
dark, it was filtered and the filtrate was concentrated to
dryness. The residue was partitioned between water and
chloroform. The organic layer was separated and the aqueous
layer was extracted with chloroform. The combined extracts
were dried and concentrated. The residue was purified by
column chromatography eluting with 30/1 chloroform/metha-
nol to give 68 mg (65%) of 30: [R]20D -94.2 (c 0.28, CHCl3); 1H
NMR (300 MHz, CDCl3) δ 7.99 (s, 1H), 7.67 (d, J ) 8.4 Hz,
1H), 6.62 (m, 1H), 5.71 (m, 1H), 5.29 (m, 1H), 5.20 (m, 1H),
3.81 (s, 3H), 3.75 (m, 1H), 3.40-3.32 (m, 6H), 3.12 (m, 1H),
2.34-2.27 (m, 3H), 2.06 (m, 2H), 1.73 (s, 3H), 1.72 (s, 3H), 1.67
(s, 3H), 1.66 (s, 3H), 1.59-1.45 (m, 4H), 1.52 (s, 9H), 1.49 (s,
9H); 13C NMR (150.9 MHz, CDCl3) δ 167.4, 163.8, 160.1, 159.8,
146.5, 142.2, 137.1, 131.7, 130.0, 120.3, 119.6, 118.2, 113.8,
112.8, 78.1, 53.4, 51.4, 50.6, 46.7, 46.4, 42.7, 42.5, 42.0, 40.1,
39.5, 39.4, 38.0, 37.0, 29.6, 28.5, 28.4, 28.0, 27.9, 25.6, 22.1,
17.9, 14.0, 13.2; ESIMS m/z 733 (M+ + Na+), 711 (M+ + H+),
610 (M+ - Boc); HRMS found m/z 710.4600 (M+ + H+),
1-Be n zyl-2-(t er t -b u t oxyca r b on yl)-3,3-d ie t h ylgu a n i-
d in e 33: 98% yield; IR (KBr) 3174, 3030, 1663 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.34 (m, 5H), 6.80 (br s, 1H), 4.39 (s, 2H),
3.67 (q, J ) 7.1 Hz, 4H), 1.51 (s, 9H), 1.15 (t, J ) 7.2 Hz, 6H);
EI-MS m/z 305 (M+), 249, 232, 205, 176, 106, 91; HRMS found
m/z 249.1491 (M+ - But + H+), C13H19N3O2 requires 249.1477.
N1-Ben zyl-N2-(ter t-bu toxyca r bon yl)-1′-p yr r olid in eca r -
boxa m id in e 34: 98% yield; IR (KBr) 3200, 3088, 1647 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.32 (m, 5H), 6.95 (br s, 1H),
4.45 (s, 2H), 3.42 (m, 4H), 1.87 (m, 4H), 1.50 (s, 9H); EI-MS
m/z 303 (M+), 247, 230, 146, 106, 91, 70, 57; HRMS found m/z
303.1901 (M+), C17H25N3O2 requires 303.1947.
1-Ben zyl-2-(ter t-bu toxycar bon yl)-3,3-diisopr opylgu an i-
1
d in e 35: 96% yield; IR (KBr) 3271, 1616 cm-1; H NMR (300
MHz, CDCl3) δ 7.39 (m, 5H), 5.00 (br s, 1H), 4.42 (s, 2H), 4.11
(m, 2H), 1.55 (s, 9H), 1.28 (d, J ) 6.3 Hz, 12H); EI-MS m/z
333 (M+), 290, 260, 234, 190, 106, 100, 91, 57; HRMS found
m/z 333.2413 (M+), C19H31N3O2 requires 333.2416.
C
38H59N7O6 requires 710.4605.
1-Ben zyl-2-(ter t-bu toxycar bon yl)-3,3-dicycloh exylgu an i-
1
d in e 36: 91% yield; IR (KBr) 3298, 1644 cm-1; H NMR (300
Ma r tin ellic Acid 1. To a solution of 30 (21 mg, 0.03 mmol)
MHz, CDCl3) δ 7.34 (m, 5H), 5.20 (br s, 1H), 4.37 (s, 2H), 3.51
(m, 2H), 1.76 (m, 8H), 1.62 (m, 6H), 1.51 (s, 9H), 1.27 (m, 4H),
0.98 (m, 2H); EI-MS m/z 413 (M+), 340, 274, 219, 182, 138,
91, 57; HRMS found m/z 413.3023 (M+), C25H39N3O2 requires
413.3042.
in MeOH (3 mL) and water (1 mL) was added NaOH (6 ng,
0.15 mmol). The suspension was refluxed for 10 h and then
neutralized with 0.1 N HCl cautiously. MeOH was removed
under reduced pressure and the aqueous was extracted with
CHCl3. The combined organic layers were dried and concen-
trated. The residue was purified by column chromatography
eluting with 5/1 chloroform/methanol to give 19 mg of the
corresponding acid. This acid was dissolved in 2 mL of
anhydrous CH2Cl2 before 0.05 mL of anisole and 0.1 mL of
(1′R)-1,3-Dib en zyl-2-(ter t-b u t oxyca r b on yl)-3-(1′-p h e-
n yleth yl)gu a n id in e 37: 93% yield; IR (KBr) 3235, 3089, 1641
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.37-7.13 (m, 13H), 6.83
(m, 2H), 5.88 (q, J ) 7.1 Hz, 1H), 5.40 (br s, 1H), 4.31 (s, 2H),
450 J . Org. Chem., Vol. 68, No. 2, 2003

Routes to Martinellic Acid
4.21 (m, 2H), 1.62 (d, J ) 7.5 Hz, 3H), 1.53 (s, 9H); EI-MS m/z
443 (M+), 369, 340, 295, 277, 264, 196, 120, 106, 91, 57; HRMS
found m/z 387.1976 (M+ - But + H+), C24H25N3O2 requires
387.1947.
EI-MS m/z 339 (M+), 283, 266, 239, 222, 192, 174, 148, 106,
91; HRMS found m/z 339.1914 (M+), C20H25N3O2 requires
339.1947.
1-Ben zyl-2-(ter t-b u t oxyca r b on yl)-3-t er t -b u t ylgu a n i-
d in e 38: 93% yield; IR (KBr) 3336, 3109, 1612 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.34 (m, 5H), 4.56 (s, 2H), 1.51 (s, 9H),
1.36 (s, 9H); EI-MS m/z 305 (M+), 249, 232, 219, 205, 193, 173,
148, 106, 91, 57; HRMS found m/z 305.2116 (M+), C17H27N3O2
requires 305.2103.
Ack n ow led gm en t. The authors are grateful to the
Chinese Academy of Sciences, National Natural Science
Foundation of China (grants 29725205 and 20132030)
and Qiu Shi Science & Technologies Foundation for
financial support. We thank Dr. K. M. Witherup of
Merck research laboratories for providing NMR spectra
of natural martinelline.
1-Ben zyl-2-(ter t-bu toxycar bon yl)-3-ph en ylgu an idin e 39:
88% yield; IR (KBr) 3350, 1643 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 10.76 (br s, 1H), 7.30 (m, 10H), 5.02 (br s, 1H), 4.61
(s, 2H), 1.55 (s, 9H); EI-MS m/z 325 (M+), 280, 263, 219, 207,
131, 77, 65, 59; HRMS found m/z 325.1839 (M+), C19H23N3O2
requires 325.1796.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds 1, 3, 4, 11, 14, 15, 18, and 30. This material is
available free of charge via the Internet at http://pubs.acs.org.
1,3-Diben zyl-2-(ter t-bu toxyca r bon yl)gu a n id in e 40: 98%
yield. IR (KBr) 3339, 3287, 3001, 1591 cm-1 1H NMR (300
;
MHz, CDCl3) δ 7.31-7.17 (m, 10H), 4.44 (m, 4H), 1.53 (s, 9H);
J O026125Z
J . Org. Chem, Vol. 68, No. 2, 2003 451