Aziridine-allylsilane-mediated total synthesis of (-)-yohimbane

Article abstract of DOI:10.1021/jo9825097

A total asymmetric synthesis of (-)-yohimbane and ent-alloyohimbane is reported. The synthesis utilizes a novel aziridine-allylsilane cyclization reaction as a key step in the synthesis. Treatment of optically pure aziridine-allylsilane 16 with BF₃ · OEt₂ provided a mixture of aminomethyl substituted carbocycles trans-20a and cis-20b in excellent yield and modest diastereoselectivity (trans/cis 3:1). Alkylation of the tosylamide followed by oxidation of the olefin in 20 provided the lactam 38, which was converted to (-)-yohimbane and ent-alloyohimbane by a Bischler-Napieralski reaction. The synthesis provided (-)-yohimbane in eight steps and 24% overall yield (from 16).

Full text of DOI:10.1021/jo9825097

J . Org. Chem. 1999, 64, 3237-3243
3237
Azir id in e-Allylsila n e-Med ia ted Tota l Syn th esis of (-)-Yoh im ba n e
Stephen C. Bergmeier* and Punit P. Seth
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy and the Comprehensive
Cancer Center, The Ohio State University, 500 West 12th Avenue, Columbus, Ohio 43210-1291
Received December 28, 1998
A total asymmetric synthesis of (-)-yohimbane and ent-alloyohimbane is reported. The synthesis
utilizes a novel aziridine-allylsilane cyclization reaction as a key step in the synthesis. Treatment
of optically pure aziridine-allylsilane 16 with BF3‚OEt2 provided a mixture of aminomethyl
substituted carbocycles trans-20a and cis-20b in excellent yield and modest diastereoselectivity
(trans/cis 3:1). Alkylation of the tosylamide followed by oxidation of the olefin in 20 provided the
lactam 38, which was converted to (-)-yohimbane and ent-alloyohimbane by a Bischler-Napieralski
reaction. The synthesis provided (-)-yohimbane in eight steps and 24% overall yield (from 16).
In tr od u ction
(-)-Yohimbane 1 and (-)-alloyohimbane 2 (Figure 1)
are members of the rauwolfia alkaloid family.1 Repre-
sentative members of this family include reserpine,
ajmalicine, and yohimbine (Figure 1). These alkaloids
have a characteristic pentacyclic ring framework with the
indole ring comprising rings A and B. Much of the
stereochemical and functional group complexity resides
on the E ring. These alkaloids possess a wide range of
interesting biological activities, including antihyperten-
sive and antipsychotic.2 Yohimbine and related com-
pounds have served as important pharmacological tools
for the differentiation of R-adrenergic receptors.3 Due to
the structural complexity and interesting biological activ-
ity of this class of alkaloids, they have piqued the interest
of synthetic organic chemists for decades.
Since the first synthesis of reserpine4 and yohimbine,5
a number of other synthetic approaches to this alkaloid
family have been reported.6 While the synthesis of
racemic 1 and 2 has been addressed on numerous
* To whom correspondence should be addressed. Tel: 614-292-5499.
E-mail: bergmeier.1@osu.edu.
(1) Woodson, R. E.; Youngken, H. W.; Schlittler, E.; Schneider, J .
A. In Rauwolfia: Botany, Pharmacognosy, Chemistry and Pharmacol-
ogy; Little Brown and Co: Boston, 1957.
(2) Scott, J . A.; Crews, F. T. J . Pharmacol. Exp. Ther. 1983, 224,
640.
F igu r e 1.
occasions,7 only two asymmetric syntheses of (-)-yohim-
bane have been reported. The first asymmetric synthesis
of (-)-yohimbane was reported in 1991.8 These authors
synthesized (-)-yohimbane utilizing an in situ 1,4-
addition/ring-closure reaction of a chiral R-sulfinyl
(3) (a) Baldwin, J . J .; Huff, J . R.; Randall, W. C.; Vacca, J . P.; Zrada,
M. M. Eur. J . Med. Chem., Chim. Ther. 1985, 20, 67. (b) Clark, R. D.;
Michel, A. D.; Whiting, R. L. Pharmacology and Structure-Activity
Relationships of R2-Adrenoreceptor Antagonists. In Progress in Me-
dicinal Chemistry; Ellis, G. P., Ed.; West Elsevier: Amsterdam, 1986;
Vol. 23, p 1.
(4) Woodward, R. B.; Bader, F. E.; Bickel, H.; Frey, A. J .; Kierstead,
R. W. Tetrahedron 1958, 2, 1.
(5) van Tamelen, E. E.; Shamma, M.; Burgstahler, A. W.; Wolinsky,
J .; Tamm, R.; Aldrich, P. E. J . Am. Chem. Soc. 1958, 80, 5006.
(6) For a recent review of syntheses of yohimbine alkaloids, see: (a)
Baxter, E. W.; Mariano, P. S. In Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Springer-Verlag: New York, 1992;
Vol. 8, pp 197-319. (b) Aube, J .; Ghosh, S. In Advances in Heterocyclic
Natural Product Synthesis; Pearson, W. H., Ed.; J AI Press, Inc.:
Greenwich, CT, 1996; Vol. 3, pp 99-150. For some more recent
approaches to this alkaloid family, see: (c) Lee, A. W. M.; Chan, W.
H.; Mo, T. Tetrahedron Lett. 1997, 38, 3001. (d) Mehta, G.; Reddy, D.
S. J . Chem. Soc., Perkin Trans. 1 1998, 2125. (e) Hanessian, S.; Pan,
J .; Carnell, A.; Bouchard, H.; Lesage, L. J . Org. Chem. 1997, 62, 465.
(f) Holzapfel, C. W.; van der Merwe, T. L. Tetrahedron Lett. 1996, 37,
2307. (g) Logers, M.; Overman, L. E.; Welmaker, G. S. J . Am. Chem.
Soc. 1995, 117, 9139. (h) Martin, S. F.; Clark, C. W.; Corbett, J . W. J .
Org. Chem. 1995, 60, 3236.
(7) For some racemic approaches to yohimbane, see: (a) Wender,
P. A.; Smith, T. E. J . Org. Chem. 1996, 61, 824. (b) Naito, T.; Miyata,
O.; Tada, Y.; Nishiguchi, Y.; Kiguchi, T.; Ninomiya, I. Chem. Pharm.
Bull. 1986, 34, 4144. (c) Martin, S. F.; Williamson, S. A.; Gist, R. P.;
Smith, K. M. J . Org. Chem. 1983, 48, 5170. (e) Kametani, T.; Suzuki,
T.; Unno, K. Tetrahedron 1981, 37, 3819. (f) Rosenmund, P.; Trommer,
W.; Dorn-Zachertz, D.; Ewerdwalbesloh, U. Liebigs Ann. Chem. 1979,
1643. (g) Morrison, G. C.; Cetenko, W. A.; Shavel, J ., J r. J . Org. Chem.
1966, 31, 2695. These workers prepared (-)-yohimbane by resolution
of racemic yohimbane. (e) van Tamelen, E. E.; Shamma, M.; Aldrich,
P. J . Am. Chem. Soc. 1956, 78, 4628. (f) Corsano, S.; Panizzi, L. Ann.
Chim. 1958, 48, 1025.
(8) (a) Hua, D. H.; Bharathi, S. N.; Takusagawa, F.; Tsujimoto, A.;
Panangadan, J . A. K.; Hung, M.-H.; Bravo, A. A.; Erpelding, A. M. J .
Org. Chem. 1989, 54, 5659. (b) Hua, D. H.; Bharathi, S. N.; Panan-
gadan, J . A. K.; Tsujimoto, A. J . Org. Chem. 1991, 56, 6998.
10.1021/jo9825097 CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/13/1999

3238 J . Org. Chem., Vol. 64, No. 9, 1999
Bergmeier and Seth
Sch em e 1
Sch em e 3
Sch em e 2
a hydroboration/oxidation sequence. The 3-ethylindole
group will have to be added by an alkylation to either
the olefin 12 (R′ ) H) or ester 11 (R′ ) H). The olefin 12
is readily accessible in enantiomerically pure form via
our aziridine-allylsilane cyclization.
Resu lts a n d Discu ssion
Our initial synthetic efforts were directed toward
developing a convenient synthesis of enantiopure aziri-
dine-allylsilane 16 (Scheme 3). Our first-generation
synthesis of this type of molecule was racemic and
involved two low-yielding steps to introduce both the
aziridine and the allylsilane moeities.10 After exploring
a few other routes, we realized that 16 could be synthe-
sized by the reaction of an aziridine 15 with an appropri-
ate organometallic reagent 14.12 While this was a useful
method to provide a quick access to chiral 16 (>97% ee),
we could not obtain reproducible yields when the reaction
was carried out on a scale >2 mmol. Hence, we decided
to synthesize 16 via a stepwise process starting from the
aziridine 17.12 Reaction with the cuprate 14 provided the
ring-opened intermediate 18 in almost quantitative yield.
Deprotection of the silyl ether using nBu4NF provided the
alcohol 19, which was then converted to the aziridine 16
via a Mitsunobu reaction.13 This sequence provided us
with an equivalent yield of 16 (83% from 17) as compared
to the single-step procedure. More importantly, this
sequence could be conveniently carried out on a 5 mmol
or greater scale.
ketimine anion with an ene ester. Recently, Aube pub-
lished an elegant oxaziridine rearrangement approach
to this alkaloid family.9
We recently communicated a novel intramolecular
cyclization reaction between aziridines and allylsilanes10
(Scheme 1). The product of this reaction is an amino-
methyl-substituted carbocycle 7. We envisioned that
amino olefins such as 7 could be extremely useful for the
asymmetric synthesis of alkaloids, especially the rau-
wolfia family. To demonstrate the synthetic utility of
these amino olefins, we report here the use of this
cyclization reaction as a key step in the synthesis of (-)-
yohimbane as a means to developing a general synthetic
route to this alkaloid family.
Retr osyn th etic An a lysis
The aziridine 16 was then cyclized by treatment with
BF3‚OEt2 (300-400 mol %) to provide the amino olefins
trans-20a and cis-20b (Scheme 4) as an inseparable
mixture (diastereoselectivity 2.8:1-2:1).14 A number of
different Lewis acids were used in an attempt to improve
the stereoselectivity of the reaction. Unfortunately, use
The lactam 10 is a well-known intermediate for the
final cyclization to form the C ring of the pentacyclic
compound 9 (Scheme 2). This cyclization is readily done
by a Bischler-Napieralski reaction.11 The lactam 10
should be accessible from the ester 11 (where R′ is either
H or 3-ethylindole) by removal of the tosyl group. The
ester 11 can, in turn, be prepared from the olefin 12 via
(12) Bergmeier, S. C.; Seth, P. P. J . Org. Chem. 1997, 62, 2671.
(13) (a) Mitsunobu, O. Synthesis 1981, 1-28. (b) Huges, D. L. The
Mitsunobu Reaction. In Organic Reactions; Paquette, L., Eds.; J ohn
Wiley & Sons: New York, 1992; Vol. 42, p 335.
(14) The stereoselectivity of the reaction was dependent on the
temperature at which the Lewis acid was added to the reaction.
Typically, when BF3‚OEt2 was added to the reaction at -78 °C and
the reaction was allowed to warm to room temperature gradually and
then stirred for 24 h, the ratio of 20a :20b was observed to be 2.8:1.
However when the BF3‚OEt2 was added to the reaction at 0 °C and
the reaction then allowed to warm to room temperature and stirred
for 24 h, the ratio of 20b:20b was observed to be ca. 2:1.
(9) (a) Aube, J . Tetrahedron Lett. 1988, 29, 4509. (b) Aube, J .; Wang,
Y.; Hammond, M.; Tanol, M.; Takusagawa, F.; Vander Velde, D. J .
Am. Chem. Soc. 1990, 112, 4879. (c) Aube, J .; Ghosh, S.; Tanol, M. J .
Am. Chem. Soc. 1994, 116, 9009.
(10) Bergmeier, S. C.; Seth, P. P. Tetrahedron Lett. 1995, 36, 3793.
(11) Whaley, W. M.; Govindachari, T. R. The preparation of 3,4-
dihydroisoquinolines and related compounds by the Bischler/Napier-
alski reaction. In Organic Reactions; Adams, R., Ed.; J ohn Wiley &
Sons: New York, 1951; Vol. 6, p 74.

Total Synthesis of (-)-Yohimbane
J . Org. Chem., Vol. 64, No. 9, 1999 3239
Sch em e 4
the N-tosyl lactams 24 (47%) and 25 (22%), which were
separable by flash chromatography. The stereochemistry
of these lactams was then confirmed by examination of
coupling constants and by NOE spectroscopy.
In lactam 24, hydrogens Ha-Hf showed up as distinct
1
signals in the H NMR spectrum. Due to the trans ring
fusion, the coupling constants J HaHd (11.5 Hz) and J HbHe
(11.8 Hz) were large (diaxial coupling constants). In
comparison, the coupling constants between J HaHc (4.5
Hz) and J HbHf (4.9 Hz) were small (axial-equatorial
coupling constants). Hd also showed an NOE to Hb (4.2%)
but not to Ha, while Hc showed an NOE to Ha (6.1%) but
not to Hb, further confirming the trans ring fusion.
In lactam 25, hydrogens Ha-Hd showed up as distinct
signals in the 1H NMR spectrum. Due to the cis ring
fusion, the dihedral angle between both Ha-Hc and Ha-
Hd should be small. As a result, the coupling constants
between J HaHc (6.3 Hz) and J HaHd (5 Hz) were smaller and
of similar magnitude. Irradiation of Hc in the NOE
experiment showed enhancements in the signals for both
Ha (6.6%) and Hb (2.1%), indicating a cis relationship
between these protons and consequently confirming the
cis ring fusion in 25.
The next step in the synthesis involved alkylation of
the tosylamide 20 with indole 26.19 Although this trans-
formation appeared fairly straightforward, it proved to
be rather difficult (Scheme 7). Reaction of the indole 26
with 20 did not provide any of the desired alkylated
product. Instead only the vinyl indole 27 was obtained
along with unreacted 20. Similar results were obtained
even when a large excess of the bromide 26 was used. A
number of different bases and solvents were also tried
without any success.
We next attempted the coupling by means of a Mit-
sunobu reaction20 between the alcohol 28 and the tosyl-
amide 20. Once again, the only product obtained was the
unreacted tosylamide. Use of a large excess of reagents
and different reaction conditions also failed completely.
The coupling was also attempted by utilizing the chlo-
rides 2921 and 3022 again with no success. We therefore
turned our attention toward deprotection of the tosyl-
amide 20 with the intention of alkylating the amine 31,
which we thought would be relatively facile. A number
of standard protocols for the deprotection of the tosyl
group including Na/NH3,23 SmI2,24 and HBr/phenol25 were
attempted. All of these resulted in decomposition of the
starting tosylamide. The desired amine was only obtained
in trace amounts from the above reactions. We then
decided to examine leaving groups other than bromide
in the alkylation reaction. To this end, the mesylate 32
of stronger Lewis acids such as TiCl4 and SnCl4 or Lewis
acids with strongly nucleophilic counterions such as
MgBr2 resulted in opening of the aziridine ring with the
Lewis acid counterion even at -78 °C. Use of TMSOTf
did provide us with some of the desired product, but this
was usually accompanied by protodesilyation as well as
formation of some other unidentified products. Use of
weaker Lewis acids such as Ti(OiPr)4, Yb(OTf)3, and Zn-
(OTf)2 did not result in any reaction even at elevated
temperatures. Use of protic acids such as CF3CO2H
resulted in decomposition. Use of solvents other than
CH2Cl2 was also unsuccessful.
The formation of the major trans isomer could be
explained as occurring via a chairlike conformation
(Scheme 5). Here, the aziridine and the allylsilane
arrange themselves in an equatorial orientation (confor-
mation A). This arrangement reduces the unfavorable
steric interactions that are seen in conformation B. An
alternate arrangement, in which the allylsilane is in an
axial arrangement, would seem to be precluded due to
A(1,3) strain.15 Coordination of the Lewis acid with the
aziridine causes polarization of the more substituted
C-N bond of the aziridine ring. This induces nucleophilic
attack by the allylsilane to form the positively charged
intermediate 21, which can then undergo an elimination
reaction to provide 20a .16 The aziridine ring opening
takes place in an SN2 fashion, with approach of the
nucleophile being anti to the aziridine ring. The forma-
tion of the minor cis isomer 20b could be explained as
occurring via conformation B. In this conformation, the
aziridine adopts an axial conformation. This results in
unfavorable steric interactions, culminating in the for-
mation of the cis-fused carbocycle 20b (minor product).
The stereochemistry of the trans- and the cis-fused
carbocycles was previously assigned by us using NOE and
NOESY spectroscopy.10 To unambiguously assign the
stereochemistry of 20a and 20b, we first attempted to
separate the diastereomeric sulfonamides by HPLC.
While we could separate 20a ,b on an analytical scale,
the HPLC procedure was not suitable for separation of
20a ,b on a preparative scale.17 We therefore decided to
convert them to the lactams 24 and 25, respectively
(Scheme 6). To this end, the olefin of 20 was hydroborated
using 9-BBN to provide the primary alcohol 23 as the
exclusive product. The alcohol 23 was then oxidized18 to
(17) In our previous work,10 we assigned the stereochemistry of a
mixture of 20a and 20b using NOE and NOESY spectroscopy. Since
then, we have developed an HPLC method for the baseline separation
of these diastereomers on an analytical scale. Unfortunately, all of our
attempts to separate these diastereomers on a preparative scale were
not successful, as we could load only less than 1 mg of sample and
still not obtain separation that was seen on an analytical scale.
(18) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J . Org. Chem. 1981, 46, 3936.
(15) Synclinal transition states (allylsilane equatorial) are preferred
over antiperiplanar transition states (allylsilane axial) in intramo-
lecular reactions of allylsilanes.
A possible explanation for this
preference could be the unfavorable A(1,3) interaction between the allylic
protons of the allylsilane and axial hydrogen of the forming ring when
the allylsilane is in an axial orientation. (a) Lolkema, L. D. M.; Semeyn,
C.; Ashek, L.; Hiemstra, H.; Speckamp, W. N. Tetrahedron 1994, 50,
7129. (b) Mann, A.; Nativi, C. Taddei, M. Tetrahedron Lett. 1988, 29,
3247. For some more examples of intramolecular reactions of allylsi-
lanes, see: (c) Fleming, I.; Barbero, A.; Walter, D. Chem. Rev. 1997,
97, 2063.
(19) Trost, B. M.; Quale, P. J . Am. Chem. Soc. 1984, 106, 2469.
(20) Tsunoda, T.; Yamamoto, H.; Goda, K.; Ito, S. Tetrahedron Lett.
1996, 37, 2457.
(21) Hochstein, F. A.; Paradies, A. M. J . Am. Chem. Soc. 1957, 79,
5735.
(22) Bergman, J .; Backvall, J .-E.; Lindstrom, J .-O. Tetrahedron
1973, 29, 971.
(23) Yamazaki, N.; Kibayashi, C. J . Am. Chem. Soc. 1989, 111, 1396.
(24) Vedejs, E.; Lin, S. J . Org. Chem. 1994, 59, 1602.
(25) Roemmele, R. C.; Rapoport, H. J . Org. Chem. 1988, 53, 2367.
(16) Hosomi, A.; Sakurai, H. J . Am. Chem. Soc. 1977, 99, 1673. (b)
Schinzer, D. Synthesis 1988, 263.

3240 J . Org. Chem., Vol. 64, No. 9, 1999
Bergmeier and Seth
Sch em e 5
Sch em e 6
Sch em e 7
was prepared from the alcohol 28. To our delight, this
reaction worked extremely well to provide us with the
alkylated product 33 in excellent yield.26 Although we did
obtain some amount of the vinyl indole 27 from the
reaction, this could be rectified by using a slight excess
of the mesylate 32.
With olefin 33 in hand, all that remained to complete
the synthesis was oxidation of the olefin followed by a
Bischler-Napieralski reaction. The olefin of 33 was
hydroborated using 9-BBN to provide the alcohol 34
(Scheme 8). Use of BH3‚THF provided mixtures of the
primary and secondary alcohols. The next step in the
synthesis involved oxidation of the alcohol 34 to the
carboxylic acid 36. A number of different oxidants were
available for this purpose.27 We initially decided to use
RuO2 as our oxidizing agent.18,28 In our hands, this
oxidizing system gave very poor results. The major
products of this reaction appeared to be the corresponding
aldehyde, which showed considerable decomposition in
the aromatic region of the H NMR spectra of the crude
1
product. A number of other reaction conditions including
J ones,29 TEMPO,30 CrO3-acetic anhydride31 were also
attempted but without success. The primary product seen
with these oxidants was the aldehyde.
Due to the poor results obtained, we decided to attempt
this transformation in a stepwise fashion. The alcohol
34 was oxidized to the aldehyde 35 using the Swern
conditions32 in excellent yield. The oxidation was also
successful when DMP33 or PCC34 was used as the oxidant.
However, the Swern conditions were found to give the
best results. We then attempted to oxidize the aldehyde
(26) The best results for the alkylation reaction were obtained when
DMF was used straight from the bottle. Use of DMF that had been
distilled over BaO resulted in lower yields and longer reaction times.
Also, under anhydrous conditions, use of KH instead of K2CO3 resulted
in lower yields of the alkylated product.
(27) (a) Larock, R. C. In Comprehensive Organic Transformations.
A guide to functional group preparations; VCH Publishers: New York,
1989; pp 834-841.
(28) (a) Behrens, C. H.; Sharpless, K. B. J . Org. Chem. 1985, 50,
5696. (b) Paquette, L. A.; Dressel, J .; Pansegrau, P. D. Tetrahedron
Lett. 1987, 28, 4965.
(29) Millar, J . G.; Oehlschlager, A. C.; Wong, J . W. J . Org. Chem.
1983, 48, 4404.
(30) Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J . Org. Chem.
1987, 52, 2559.
(31) Corey, E. J .; Samuelsson, B. J . Org. Chem. 1984, 49, 4735.
(32) Mancuso, A. J .; Huang, S.-L.; Swern., D. J . Org. Chem. 1978,
43, 2480.

Total Synthesis of (-)-Yohimbane
J . Org. Chem., Vol. 64, No. 9, 1999 3241
Sch em e 8
Sch em e 9
novel aziridine-allysilane cyclization reaction as the key
step in the synthesis to form the E ring. By incorporating
appropriate functionality along the tether between the
aziridine and the allylsilane, this cyclization should also
serve as an effective route for the synthesis of more
complex members of the rauwolfia alkaloid family.
Exp er im en ta l Section 40
(8R)-1-(Tr im et h ylsilyl)-8-[(4-m et h ylp h en yl)su lfon yl]-
a m in o-9-[(ter t-bu tyld im eth yl)silyl]oxon on -2-en e (18). t-
BuLi (19.5 mL of a 1.58 M solution in pentane, 30.8 mmol)
was added dropwise to a solution of 1-(trimethylsilyl)-6-
iodohex-2-ene12 (3.95 g, 14 mmol) in Et2O (28 mL) at -78 °C.
The reaction mixture was then allowed to stir at -78 °C for
10 min, after which it was allowed to warm to room temper-
ature and stirred for an additional 60 min. The reaction
mixture was then recooled to -78 °C. In a separate flask, CuI
(0.95 g, 5 mmol) was dissolved in n-Bu3P (5.8 mL, 23.5 mmol)
and Et2O (2 mL). The slightly turbid solution of CuI/n-Bu3P
in Et2O was then transferred to the organolithium prepared
above using additional Et2O (26 mL). The yellowish cuprate
solution thus formed was warmed to -40 °C and stirred for
10 min, after which it was recooled to -78 °C. The aziridine
1712(1.71 g, 5 mmol) was dissolved in Et2O (2 mL) and added
to the reaction mixture via cannula. The reaction was stirred
at -78 °C for 30 min, after which it was warmed to room
temperature and stirred for another 30 min. The reaction was
quenched by adding saturated NH4Cl solution and the organic
layer washed with saturated NH4Cl and brine, dried (MgSO4),
and concentrated. Chromatography (4% EtOAc in hexanes-
15% EtOAc in hexanes) provided 18 (2.42 g, 97%) as a colorless
oil: Rf 0.3 (15% EtOAc in hexanes); [R]D +20.9° (c 2.1, EtOAc);
1H NMR δ 7.69 (d, 2H, J ) 8.26), 7.22 (d, 2H, J ) 8.05), 5.33-
5.13 (m, 2H), 4.76 (d, 1H, J ) 8.32), 3.37 (dd, 1H, J ) 3.25,
9.97), 3.26 (dd, 1H, J ) 4.39, 9.97), 3.15 (m, 1H), 2.36 (s, 3H),
1.85 (m, 2H), 1.37 (d, overlapped, 2H, J ) 7.76), 1.46-1.1 (m,
6H), 0.78 (s, 9H), -0.06 (s, 9H), -0.09 (s, 3H), -0.1 (s, 3H);
13C NMR δ 143.1, 138.4, 129.5, 127.2, 127, 125.4, 64.1, 54.9,
32, 29.4, 26.8, 25.8, 25.3, 21.4, 18.4, 18.2, -1.8, -5.7. Anal.
Calcd for C25H47NO3Si2S 0.25 H2O: C, 59.78; H, 9.53; N, 2.78.
Found: C, 59.69; H, 9.52; N, 2.67.
to the acid using RuCl3-NaIO427 and NaOCl35 but again
without any success. The aldehyde was finally oxidized
to the acid using KMnO4 in buffered phosphate solution36
in good yield. The crude acid 36 was then readily
converted to the methyl ester 37 using methyl chloro-
formate and triethylamine37 (65% from 35) or Me3-
38
SiCHN2 (80% from 35).
The next crucial step in the synthesis was deprotection
of the two tosylamide protecting groups in 37. We first
attempted the deprotection using SmI2.24 This reaction
did not provide us with the desired product. We then
attempted the reaction using sodium naphthalenide.39
This procedure did not provide us with the corresponding
deprotected ester but instead provided us with the lactam
38, which was now set for a ring closure to provide us
with our final product. The lactam 38 was then subjected
to the Bischler-Napieralski conditions to provide (-)-
yohimbane and ent-alloyohimbane (Scheme 9) as a
mixture that could be easily separated by chromatogra-
phy on silica gel, thus completing our total synthesis. The
analytical data of our synthesized product were in
complete agreement with those reported in the liter-
ature.7g,9c
(40) Thin-layer chromatography (TLC) was performed on Whatman
precoated silica gel F254 aluminum foil. Visualization was accomplished
with UV light and/or phosphomolybdic acid solution followed by
heating. Purification of the reaction products was carried out by flash
column chromatography using glass column dry packed with silica gel
(230-400 mesh ASTM) according to the method of Still.43 1H NMR
and 13C NMR spectra referenced to TMS were recorded using a Bruker
AF 250 or Bruker DRX 400 model spectrometer. NOE experiments
were carried out using a Bruker DRX 400 spectrometer. Unless noted,
all spectra were recorded in CDCl3. Data are reported as follows:
chemical shift in ppm from internal standard tetramethylsilane on the
δ scale, multiplicity (b ) broad, s ) singlet, d ) doublet, t ) triplet, q
) quartet, and m ) multiplet), integration, coupling constant (Hz).
All reactions were carried out under an atmosphere of nitrogen unless
In conclusion, we have synthesized (-)-yohimbane in
eight steps and 24% overall yield (from 16), utilizing a
(33) (a) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155. (b)
Meyer, S. D.; Schreiber, S. L. J . Org. Chem. 1994, 59, 7550. (c) Ireland,
R. E.; Liu, L. J . Org. Chem. 1993, 58, 2899.
(34) Corey, E. J .; Suggs, J . W. Tetrahedron Lett. 1975, 15, 2647.
(35) Stevens, R. V.; Chapman, K. T.; Stubbs, C. A.; Tam, W. W.;
Albizati, K. F. Tetrahedron Lett. 1982, 23, 4647.
(36) Abiko, A.; Roberts, J . C.; Takemasa, T.; Masamune, S. Tetra-
hedron Lett. 1986, 27, 4537.
(37) Kim. S.; Kim, Y. C.; Lee, J . I. Tetrahedron Lett. 1983, 24, 3365.
(38) Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull.
1981, 29, 1475.
(39) J i, S.; Gortler, L. B.; Waring, A.; Battisti, A.; Bank, S.; Closson,
W. D. Wriede, P. J . Am. Chem. Soc. 1967, 89, 5311.
specified otherwise. Glassware was flame dried under a flow of
nitrogen. Tetrahydrofuran and diethyl ether were distilled over
Sodium/benzophenone ketyl immediately prior to use. Dichloromethane,
DME, and benzene were distilled over CaH2 prior to use. Exact mass
measurements recorded in the electron impact (EI) or fast atom
bombardment (FAB) modes were determined at The Ohio State
University Campus Chemical Instrument Center with a Kratos MS-
30 mass spectrometer. Combustion analyses were performed at
Quantitative Technologies Inc., Whitehouse, NJ . Optical rotations were
recorded using a Perkin-Elmer 241 model polarimeter.

3242 J . Org. Chem., Vol. 64, No. 9, 1999
Bergmeier and Seth
(R)-2-[7-(Tr im eth ylsilyl)h ept-5-en ]-N-[(4-m eth ylph en yl)-
su lfon yl]a zir id in e (16). n-Bu4NF (5.5 mL of a 1 M solution
in THF, 5.5 mmol) was added dropwise over 5 min to a solution
of the alcohol 18 (2.42 g, 4.85 mmol) in THF (5 mL) at 0 °C.
The reaction mixture was stirred for 30 min, after which it
was diluted with water. The aqueous layer was then extracted
with EtOAc (3 × 10 mL), and the combined organic layers
washed with brine, dried (MgSO4), and concentrated. The
crude product thus obtained was dried under vacuum (2
mmHg) overnight and used without any further purification.
The crude alcohol 19 obtained from above was transferred to
a flame-dried flask containing Ph3P (1.34 g, 5.11 mmol), using
THF (19 mL). The resulting solution was cooled in an ice bath.
Diethylazodicarboxylate (0.81 mL, 5.11 mmol) was added to
the reaction over 5 min via a syringe, and the reaction mixture
was then allowed to stir for 3 h after which the solvent was
removed under vacuum. The resulting thick oil was triturated
with hexanes resulting in precipitation of a white solid (Ph3-
PO), which was filtered to provide a solution that was then
concentrated. Chromatography (8% EtOAc in hexanes) pro-
vided the aziridine 16 (1.51 g, 86% from 18) as a colorless oil.
The analytical data for 16 were identical to those reported
earlier.12
(1S,2R)-1-Eth en e-2-[(4-m eth ylp h en yl)su lfon yl]a m in o-
m eth ylcycloh exa n e (20a ) a n d (1R,2R)-1-Eth en e-2-[(4-
m eth ylp h en yl)su lfon yl]a m in om eth ylcycloh exa n e (20b).
Freshly distilled BF3‚OEt2 (1.5 mL, 12.3 mmol) in CH2Cl2 (3
mL) was added to a solution of the aziridine 16 (1.5 g, 4.1
mmol) in CH2Cl2 (38 mL) at 0 °C over 5 min. The reaction
mixture was stirred at 0 °C for 60 min, after which it was
warmed to room temperature and stirred for 18 h. The reaction
mixture was quenched by the addition of saturated K2CO3
solution. The organic layer was then washed with saturated
K2CO3, brine, dried (MgSO4), and concentrated. Chromatog-
raphy (12% EtOAc in hexanes) provided an inseparable
mixture of 20a :20b (2:1, 1.13 g, 94%) as a colorless oil.
Analytical data were identical to those reported earlier.10
(1S,2R)-1-(2-Hyd r oxyeth yl)-2-[(4-m eth ylp h en yl)su lfon -
yl]a m in om eth ylcycloh exa n e (23a ) a n d (1R,2R)-1-(2-Hy-
d r oxyeth yl)-2-[(4-m eth ylp h en yl)su lfon yl]a m in om eth yl-
cycloh exa n e (23b). 9-BBN (5.5 mL of a 0.5 M solution in
THF, 2.7 mmol) was added to a solution of the olefin 20 (0.2
g, 0.68 mmol) in THF (1.4 mL). The reaction was then stirred
at room temperature for 3.5 h. The reaction mixture was cooled
in an ice bath, and the excess 9-BBN was quenched with EtOH
(1.6 mL) and stirred for 5 min followed by addition of 6 N
NaOH (0.54 mL) and H2O2 (1 mL, 30% solution). The reaction
mixture was refluxed for 60 min and cooled to room temper-
ature. The reaction mixture was then diluted with water and
extracted with EtOAc (3 × 10 mL). The combined organic
layers were washed with brine, dried (MgSO4), and concen-
trated. Chromatography (35% EtOAc in hexanes) provided 23
(0.19 g, 90%, 2:1 mixture of trans and cis isomers): Rf 0.24
(35% EtOAc in hexanes); 1H NMR δ 7.69 (d, 2H, J ) 8.26),
7.22 (d, 2H, J ) 8.15), 5.88* (t, 1H, J ) 6.41), 5.67 (t, 1H, J )
6.43), 3.7-3.5 (m, 2H), 2.9-2.4 (m, 3H), 2.36 (s, 3H), 1.85-
1.09 (m, 10H), 1.08-0.8 (m, 1H); 13C NMR (* indicates signal
arising from minor cis isomer) δ 143, 142.9*, 137.1*, 137, 129.5,
126.9, 61*, 60.2, 46.1, 44.2*, 41.4, 39.4*, 35.5, 35.4, 32.2*, 31.6,
30.1, 28.8*, 26.2*, 25.6, 25.5, 24.1*, 22.1*, 21.3. Anal. Calcd
for C16H25NO3S: C, 61.7; H, 8.09; N, 4.49. Found: C, 61.9; H,
8.37; N, 4.1.
4.16 (dd, 1H, J ) 4.52, 11.73), 3.16 (t, 1H, J ) 11.46), 2.45
(partially overlapped dd, 1H, J ) 4.9, 17.97), 2.42 (s, 3H), 2.05
(dd, 1H, J ) 11.75, 17.83), 1.9-1.65 (m, 4H), 1.6-0.8 (m, 6H);
13C NMR 169.7, 144.5, 136.1, 129.1, 128.5, 52.1, 40.9, 38.5,
36.5, 32.1, 29.3, 25.1, 25, 21.5. Analytical data for 25: Rf 0.51
(35% EtOAc in hexanes); [R]D ) +27.3° (c 1.35, EtOAc); 1H
NMR δ 7.86 (d, 2H, J ) 8.41), 7.28 (d, 2H, J ) 8.58), 3.95 (dd,
1H, J ) 6.26, 12.3), 3.79 (dd, 1H, J ) 5, 12.3), 2.42 (s, 3H),
2.35 (partially overlapped dd, 2H, J ) 2.95, 6.93), 1.9 (m, 2H),
1.7-1.2 (m, 8H); 13C NMR δ 170, 144.6, 136.2, 129.2, 128.6,
49.3, 36.7, 33.4, 32.1, 28.2, 25.9, 23.1, 21.9, 21.6. Anal. Calcd
for C16H21NO3S: C, 62.51; H, 6.89; N, 4.56. Found: C, 62.57;
H, 7.05; N, 4.36.
N-(4-Meth ylp h en yl)su lfon yl-3-[(2-m eth ylsu lfon yloxo)-
et h yl]in d ole (32). tert-Butyldimethylsilyl chloride (7 g, 46
mmol) in CH2Cl2 (10 mL) was added dropwise over 20 min to
a
cold solution (0 °C) of tryptophol41 (6.8 g, 42 mmol),
triethylamine (8.8 mL, 63 mmol), and DMAP (0.5 g, 4.2 mmol)
in CH2Cl2 (45 mL). The reaction mixture was stirred for 12 h,
after which it was diluted with CHCl3 (50 mL), and the organic
phase was washed with 1 M HCl, saturated NaHCO3, and
brine, dried (MgSO4), and concentrated to provide O-(tert-
butyldimethylsilyl)tryptophol (18 g, crude): 1H NMR δ 7.9 (br,
1H), 7.56 (d, 1H, J ) 8.75), 7.25 (m, 3H), 6.95 (s, 1H), 3.85 (t,
2H, J ) 7.5), 2.94 (t, 2H, J ) 7.5), 0.92 (s, 9H), 0.0 (s, 6 H).
The crude O-(tert-butyldimethylsilyl)tryptophol (18 g, 42 mmol),
tosyl chloride (9.8 g, 51 mmol), and n-Bu4NHSO442 (0.3 g, 0.84
mmol) were dissolved in toluene (250 mL). The resulting
solution was vigorously stirred with 10% NaOH solution (500
mL) for 18 h, after which the phases were separated and the
organic phase was washed with water (200 mL), dried (MgSO4)
and concentrated to provide N-tosyl-O-(tert-butyldimethylsi-
lyl)tryptophol (9.5 g, crude): 1H NMR δ 8.0 (d, 1H, J ) 8.75),
7.74 (d, 2H, J ) 8.31), 7.48-7.16 (m, 6H), 3.85 (t, 2H, J )
7.5), 2.94 (t, 2H, J ) 7.5), 2.28 (s, 3 H), 0.9 (s, 9H), 0.0 (s, 6H).
The crude N-tosyl-O-(tert-butyldimethylsilyl)tryptophol (9.5 g,
22 mmol) was dissolved in THF (25 mL), and the solution was
cooled in an ice bath. n-Bu4NF (24 mL, 24 mmol) was added
to the above solution, and the reaction mixture was stirred
for 4 h. The reaction mixture was stopped by addition of water
(50 mL) and extracted with EtOAc (2 × 25 mL). The combined
organic phases were washed with brine, dried (MgSO4), and
concentrated to provide N-tosyltryptophol (6.2 g, crude): 1H
NMR δ 8.0 (d, 1H, J ) 8.75), 7.74 (d, 2H, J ) 8.31), 7.48-7.16
(m, 6H), 3.85 (t, 2H, J ) 7.5), 2.94 (t, 2H, J ) 7.5), 2.28 (s, 3
H), 2.12 (br, 1H). The crude N-tosyltryptophol (6.2 g, 19.7
mmol), triethylamine (4.12 mL, 29.55 mmol), and DMAP (0.25
g, 2 mmol) were dissolved in CH2Cl2 (20 mL), and the resulting
solution was cooled in an ice bath (0 °C). Freshly distilled
methanesulfonyl chloride (2.48 g, 21.7 mmol) in CH2Cl2 (5 mL)
was slowly added to the solution above, and the reaction
mixture was stirred for 3 h, after which it was diluted with
CHCl3 and the organic phase was extracted with 1 M HCl,
saturated NaHCO3, and brine, dried (MgSO4), and concen-
trated. Chromatography (35% EtOAc in hexanes) provided the
mesylate 32 (7.73 g, 46% from tryptophol) as a viscous, sticky
1
oil: Rf 0.3 (35% EtOAc in hexanes); H NMR δ 7.98 (d, 1H, J
) 8.32), 7.74 (d, 2H, J ) 8.41 Hz), 7.45 (m, 2H), 7.4-7.2 (m,
4H), 4.43 (t, 2H, J ) 6.84), 3.12 (t, 2H, J ) 7), 2.83 (s, 3H),
2.32 (s, 3H); 13C NMR δ 144.9, 135.4, 135.2, 130.3, 129.9, 126.8,
125.0, 124.2, 123.3, 119.1, 117.3, 113.8, 68.4, 37.4, 25.2, 21.4;
HRMS for C18H19NO5S2 calcd 393.0706, found 393.0712.
In d ole Olefin (33). K2CO3 (1.41 g, 10.2 mmol) was added
to a solution of the tosylamide 20 (0.75 g, 2.5 mmol) and the
mesylate 32 (2 g, 5.11 mmol) in DMF (7 mL), and the reaction
mixture was then warmed to 70 °C and stirred for 24 h. The
reaction mixture was then diluted with water and extracted
with EtOAc (3 × 10 mL). The combined organic layers were
washed with water and brine, dried (MgSO4), and concen-
trated. Chromatography (25% hexanes in CHCl3) provided 33
(4a S,8a R)-N-[(4-Meth ylp h en yl)su lfon yl]d eca h yd r oiso-
qu in olin -3-on e (24) a n d (4a R,8a R)-N-[(4-Meth ylp h en yl)-
su lfon yl]d eca h yd r oisoqu in olin -3-on e (25). RuCl3‚3H2O
(4.4 mg, 0.02 mmol) in H2O (2 mL) was added to a mixture of
the alcohol 23 (165 mg, 0.53 mmol) in CCl4/CH3CN (1:1, 2.4
mL) and NaIO4 (0.41 g, 1.9 mmol). The reaction mixture was
then stirred for 18 h, after which it was diluted with water (5
mL), the aqueous layer was extracted with CHCl3 (2 × 5 mL),
and the combined organic layers were dried (MgSO4) and
concentrated. Chromatography (20% EtOAc in hexanes) pro-
vided 24 (78 mg, 47%) and 25 (36 mg, 22%). Analytical data
for 24: Rf 0.6 (35% EtOAc in hexanes); [R]D ) +31.4° (c 1.52,
EtOAc); 1H NMR δ 7.9 (d, 2H, J ) 8.36), 7.3 (d, 2H, J ) 8.31),
(41) Tryptophol is commercially available (Aldrich) or can be easily
prepared by a two-step process from indole.21
(42) Illi, V. O. Synthesis, 1979, 136.
(43) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

Total Synthesis of (-)-Yohimbane
J . Org. Chem., Vol. 64, No. 9, 1999 3243
(1.32 g, 92%, 3:1 mixture of trans and cis isomers) as a foamy
solid: Rf 0.33 (20% hexanes in CHCl3); 1H NMR (400 MHz,
CDCl3), δ 7.89 (d, 1H, J ) 8.25), 7.69 (d, 2H, J ) 8.21), 7.41
(m, 1H), 7.27, 7.14 (m, 7H), 5.8* (m, 1H), 5.43 (m, 1H), 4.97-
4.83 (m, 2H), 3.3-2.68 (m, 6H), 2.35 (s, 3H), 2.27 (s, 3H), 1.9
(m, 1H), 1.59-0.5 (m, 11H); 13C NMR (* indicates signal
arising form minor cis isomer) δ 144.7, 143.1*, 143, 142.4,
138.6*, 136.6, 136.5*, 135.2, 135.1, 130.4, 129.7, 129.5, 127.1,
127*, 126.9*, 126.7, 124.6, 123.4, 123.3*, 123, 119.2, 119.1,
115.6*, 114.6, 113.6, 53.4, 51.4*, 48.5, 46.3, 41.8*, 40.1, 38.3*,
33.4, 30.4*, 29.8, 25.8*, 25.5, 25.4, 25*, 24.8, 24.1*, 22.3*, 21.4,
21.3. Anal. Calcd for C33H38N2O4S2‚0.5H2O: C, 66.08; H, 6.65;
N, 4.67. Found: C, 66.14; H, 6.4; N, 4.39.
a 1 M solution in hexanes, 0.64 mmol) was then added to the
reaction mixture via a syringe, and the whole was stirred for
30 min, after which the reaction mixture was diluted with
water and extracted with EtOAc (2 × 5 mL). The combined
organic layers were then washed with brine, dried (MgSO4),
and concentrated. Flash chromatography (25% EtOAc in
hexanes) provided the ester 37 (0.25 g, 80% from 35) as a white
foam: Rf 0.32 (25% EtOAc in hexanes); 1H NMR δ 7.94 (d,
1H, J ) 7.15), 7.72 (d, 2H, J ) 8.38), 7.65 (d, 2H, J ) 8.25),
7.48 (d, 1H, J ) 6.91), 7.3-7.15 (m, 8H), 3.61* (s, 3H), 3.6 (s,
3H), 3.4-2.8 (m, 5H), 2.38 (s, 3H), 2.34-2.1 (m, overlapped,
2H), 2.29 (s, 3H), 1.9-0.9 (m, 9H). 13C NMR (* indicates signal
arising form minor cis isomer) δ 173.3*, 173.1, 144.7, 143.3,
143.2, 136.3, 136.2*, 135.2*, 135.1, 130.4, 129.7, 129.6*, 129.5,
127.1*, 127.1, 126.7, 124.7, 123.5*, 123.4, 123.1, 119.2, 119.1,
113.6, 52.6, 51.4*, 51.3, 48.6, 48.3*, 39.7, 38.4, 37.1, 37*, 34.3*,
31.9, 29.4, 29.1*, 25.8*, 25.2, 25.1*, 24.9, 24.8, 23*, 22.9*, 21.4,
21.3. Anal. Calcd for C34H40N2O6S2‚0.5H2O: C, 63.23; H, 6.4;
N, 4.33. Found: C, 63.47; H, 6.45; N, 4.17.
In d ole Alcoh ol (34). 9-BBN (17.6 mL of a 0.5 M solution
in THF, 8.8 mmol) was added to a solution of the olefin 33
(1.3 g, 2.2 mmol) in THF (4 mL). The reaction mixture was
stirred at room temperature for 3.5 h. The reaction was cooled
in an ice bath, and the excess 9-BBN was quenched with EtOH
(5.2 mL) and stirred for 5 min followed by addition of 6 N
NaOH (1.8 mL) and H2O2 (3.5 mL, 30% solution). The reaction
was refluxed for 60 min and cooled to room temperature. The
reaction was then diluted with water and extracted with
EtOAc (3 × 20 mL). The combined organic layers were washed
with brine, dried (MgSO4) and concentrated. Chromatography
(35% EtOAc in hexanes) provided 34 (1.17 g, 90%, 3:1 mixture
of trans and cis isomers): Rf ) 0.32 (40% EtOAc in hexanes);
1H NMR δ 7.94 (d, 1H, J ) 7.72), 7.73 (d, 2H, J ) 8.37), 7.66
(d, 2H, J ) 8.3), 7.44 (m, 1H), 7.29-7.17 (m, 8H), 3.7-3.5 (m,
2H), 3.4-3.15 (m, 2H), 3.05-2.79 (m, 3H), 2.4 (s, 3H), 2.3 (s,
3H), 1.9-0.9 (m, 14H); 13C NMR (* indicates signal arising
form minor cis isomer) δ 144.9, 143.3, 143.2*, 136.6, 136.4*,
135.4, 135.2, 130.5, 129.8, 129.7, 127.2, 126.8, 124.7, 123.5,
123.4*, 123.2, 119.3, 113.7, 61.2*, 60.6, 53.1, 50.2*, 48.7, 48.5*,
40.1, 38.2*, 36.7, 36.1, 33.2*, 31.3*, 31.2, 29.7, 28.5*, 26*, 25.4*,
25.1, 25, 23.8*, 22.7*, 21.5, 21.4. Anal. Calcd for C33H40N2O5-
S2: C, 65.1; H, 6.62; N, 4.6. Found C, 64.8; H, 6.75; N, 4.2.
In d ole Ald eh yd e (35). Dimethyl sulfoxide (0.16 mL, 2.2
mmol) in CH2Cl2 (1 mL) was slowly added to a cold (-78 °C)
solution of freshly distilled oxalyl chloride (0.1 mL, 1.2 mmol)
in CH2Cl2 (1 mL). The resulting solution was then stirred for
45 min at -78 °C. The alcohol 34 (0.54 g, 0.88 mmol) in CH2-
Cl2 (1 mL) was then added to the reaction mixture via a
cannula and the whole stirred at -78 °C for 60 min. Et3N (0.4
mL, 3 mmol) in CH2Cl2 (1 mL) was then added to the reaction
mixture, which was then slowly allowed to warm to room
temperature over 30 min. The reaction was quenched by the
addition of a few drops of 1 M HCl and diluted with CHCl3.
The organic phase was then washed with 1 M HCl, saturated
NaHCO3, and brine, dried (MgSO4), and concentrated. Chro-
matography (30% EtOAc in hexanes) provided the aldehyde
35 (0.47 g, 88%, 3:1 mixture of trans/cis isomers): Rf 0.35 (30%
In d ole La cta m (38). Finely chopped sodium metal (66 mg,
2.9 mmol) and naphthalene (0.37 g, 2.9 mmol) were stirred in
DME (3.8 mL) for 90 min during which a greenish black
solution formed. The reaction mixture was then cooled in an
ice bath. The ester 37 (0.19 g, 0.29 mmol) in DME (2.3 mL)
was then added to the reaction mixture via cannula and the
solution stirred for 60 min. The reaction was then quenched
with water, and the aqueous layer was extracted with EtOAc.
The organic layer was then washed with brine, dried (MgSO4),
and concentrated. Chromatography (2% MeOH in CHCl3)
provided the lactam 38 (66 mg, 77%) as a light brown solid:
1
Rf 0.25 (2% MeOH in CHCl3); H NMR δ 8.27 (br, 1H), 7.67
(d, 1H, J ) 7.45), 7.35 (d, 1H, J ) 7.64), 7.21-7 (m, 4H), 3.75-
3.6 (m, 2H), 3.2-2.8 (m, 4H), 2.6-2.4 (m, 1H), 2.1-1.9 (m, 1H),
1.85-1.6 (m, 5H), 1.6-1.1 (m, 6H), 1-0.8 (m, 1H); 13C NMR
(* indicates signal arising form minor cis isomer) δ 169.6,
169.3*, 138.3, 128.3*, 127.6, 122*, 121.9, 121.9, 119.3, 118.8,
113.3, 111.1, 54.4, 51.1*, 48.1*, 48, 39.5, 38.4, 37.1, 35.2*, 33*,
32.6, 32.5*, 29.7, 28.3*, 26.5*, 25.4, 23.1*, 23, 22.6*. Anal.
Calcd for C19H24N2O‚0.75H2O: C, 73.82; H, 8.07; N, 9.06.
Found: C, 74.04; H, 8.03; N, 8.66.
(-)-Yoh im ba n e (1) a n d en t-Alloyoh im ba n e (en t-2). The
lactam 38 (39 mg, 0.13 mmol) was refluxed in freshly distilled
POCl3 (0.2 mL, 0.2 mmol) for 60 min. Benzene (1.3 mL) was
then added to the reaction mixture, which was then refluxed
for another 2.5 h. The reaction mixture was concentrated until
dryness. The residue thus obtained was taken up in MeOH
(2.4 mL), and the reaction mixture was cooled in an ice bath
followed by addition of NaBH4 (20 mg, 0.53 mmol), after which
the reaction mixture was stirred for 60 min. The reaction was
then quenched by the addition of a few drops of AcOH. The
solvent was removed in vacuo, and the residue was partitioned
between EtOAc and saturated NaHCO3 solution. The organic
phase was dried (MgSO4) and concentrated. Chromatography
(17% EtOAc, 1% Et3N, 82% toluene) provided (-)-yohimbane
(22 mg, 59%) and ent-alloyohimbane (8 mg, 22%). Analytical
data for 1: Rf 0.19 (17% EtOAc, 1% Et3N, 82% toluene); [R]D
-82.9° (c 0.38, EtOH) [lit.7g [R]D -81° (c 0.5, EtOH)]. Analytical
data for ent-2: Rf 0.24 (17% EtOAc, 1% Et3N, 82% toluene);
[R]D +146° (c 0.1, pyridine) [lit.9b [R]D of (-)-alloyohimbane
1
EtOAc in hexanes); H NMR δ 9.65 (m, 1H), 7.96 (d, 1H, J )
7.09). 7.75 (d, 2H, J ) 8.28), 7.56 (d, 2H, J ) 8.28), 7.5 (m,
1H), 7.45-7.2 (m, 8H), 3.4-3.25 (m 2H), 3.1-2.9 (m, 4H), 2.5-
2.4 (m, overlapped, 1H), 2.4 (s, 3H), 2.33 (s, 3H), 2.33-2.11
(m, overlapped, 1H), 1.9-1.6 (m, 4H), 1.5-0.9 (m, 5H); 13C
NMR (* indicates signal arising form minor cis isomer) δ
202.3*, 202.1, 144.9, 143.5*, 143.4, 136.4, 136.2*, 135.4, 135.2,
130.5, 129.9, 129.8*, 129.7, 127.2, 126.8, 124.8, 123.6, 123.5*,
123.2, 119.3, 119.2, 113.7, 53, 48.8, 48.4*, 48.1, 42.9*, 40, 37.7*,
34.9, 32.4, 30.9*, 29.6, 29.3*, 26*, 25.2, 25, 24.8, 23.7*, 22.2*,
21.5, 21.4. Anal. Calcd for C33H38N2O5S2‚0.5H2O: C, 64.36; H,
6.38; N, 4.54. Found C, 64.12; H, 6.27; N, 4.42.
1
-164° (c 0.5, pyridine)]. H and 13C NMR for (-)-yohimbane
and ent-alloyohimbane matched those previously reported.9
Ack n ow led gm en t. The authors would like to grate-
fully acknowledge J im Mobley for his help with the
HPLC separation and Dr. J . Aube (University of Kan-
In d ole Ester (37). A 1 M KMnO4 solution (3 mL) was added
to a solution of the aldehyde 35 (0.3 g, 0.45 mmol) in t-BuOH
(3 mL) containing CHCl3 (5-10 drops until 35 completely
dissolves) and 5% NaH2PO4 solution (2 mL) at 0 °C. The
reaction mixture was then stirred for 10 min and quenched
by the addition of solid Na2SO3 until the solution turned a dark
brown from the initial dark purple color. HCl (1 M) was added
to the reaction mixture until the pH of the solution was <1.
The reaction was then extracted with EtOAc (2 × 10 mL), and
the combined layers were washed with brine, dried (MgSO4),
and concentrated. The crude material was then dissolved in
MeOH (1 mL) and benzene (3.5 mL). Me3SiCHN2 (0.32 mL of
1
sas) for providing us with H NMR and 13C NMR spectra
of yohimbane and alloyohimbane.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of 1, en t-2, and 32 as well as 1H NMR spectra of 24
and 25. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O9825097