Asymmetric synthesis of the potent HIV-protease inhibitor, nelfinavir

Article abstract of DOI:10.1021/jo902048t

(Chemical Equation Presented) An asymmetric synthesis of nelfinavir is described starting from acrolein and (S)-methyl phenyl sulfoxide. The key features include (a) stereoselective preparation of a β-protected amino-γ,δ-unsaturated sulfoxide by the reaction of an α-sulfinyl carbanion with an unsaturated t-butyl sulfinylimine, (b) stereoselective bromohydrin formation using the pendant sulfoxide group as an intramolecular nucleophile, and (c) use of commercially or readily prepared inexpensive starting materials.

Full text of DOI:10.1021/jo902048t

pubs.acs.org/joc
Retrosynthetically, nelfinavir can be broken into three com-
Asymmetric Synthesis of the Potent HIV-Protease
Inhibitor, Nelfinavir
ponents: a benzoic acid derivative, central C4 core, and a
perhydroisoquinoline derivative. The preparation of the benzoic
acid2 and perhydroisoquinoline subunit3 has been described in
the literature. However, the synthesis of an appropriate C4 unit
and its coupling to the two aforementioned subunits has proved
to be challenging. Earlier approaches to the C4 core have relied
on (a) chiral pool starting materials including amino acid,4
hydroxy acid,5 and sodium erythorbate;6 (b) desymmetrization
of meso epoxide;2a,7 and (c) Michael addition as key steps.8 The
above approaches suffer from one or more of the following
drawbacks: (i) use of relatively expensive starting materials,
(ii) use of expensive reagents, (iii) incomplete regio- and stereo-
control, and (iv) many steps. In continuation of our interest
in the utilization of the sulfinyl moiety as an intramolecular
nucleophile9 for the regio- and stereoselective oxidative func-
tionalization of alkenes, we describe herein a practical
stereoselective synthesis of nelfinavir from β-protected amino-
γ,δ-unsaturated sulfoxide 6, Scheme 1 (retrosynthetic plan).
Amino alcohol 3 was envisioned to be derived from sulfoxide 4,
which in turn can be obtained from 6.
Sadagopan Raghavan,* V. Krishnaiah, and B. Sridhar†
Organic Division I, Indian Institute of Chemical Technology,
Hyderabad 500 007, India and †Lab of X-ray Crystallography,
Indian Institute of Chemical Technology,
Hyderabad-500 007, India
sraghavan@iict.res.in
Received September 23, 2009
There are only a handful of reports on the addition of
R-sulfinyl carbanions to imines.10 To the best of our knowledge
there was only a single report on the addition of R-sulfinyl
carbanion to an imine derived from an unsaturated aldehyde11
prior to our work. We have shown that the lithio anion of
(R)-methyl p-tolyl sulfoxide reacted with an N-Ts imine derived
from cinnamaldehyde,12 with only modest stereocontrol. The
first challenge toward the synthesis of nelfinavir was therefore
to prepare β-protected amino-γ,δ-unsaturated sulfoxide 6,
with good diastereoselectivity. Garcia Ruano and co-workers
reported13 a diastereoselective synthesis of β-amino sulfoxides
An asymmetric synthesis of nelfinavir is described start-
ing from acrolein and (S)-methyl phenyl sulfoxide. The
key features include (a) stereoselective preparation of a
β-protected amino-γ,δ-unsaturated sulfoxide by the
reaction of an R-sulfinyl carbanion with an unsaturated
t-butyl sulfinylimine, (b) stereoselective bromohydrin
formation using the pendant sulfoxide group as an
intramolecular nucleophile, and (c) use of commercially
or readily prepared inexpensive starting materials.
(4) Rieger, D. L. J. Org. Chem. 1997, 62, 8546.
(5) (a) Albizati, K. F.; Babu, S.; Birchler, A.; Busse, J. K.; Fugett, M.;
Grubbs, A.; Haddach, A.; Pagan, M.; Potts, B.; Remarchuk, T.; Rieger, D.;
Rodriguez, R.; Shanley, J.; Szendroi, R.; Tibbetts, T.; Whitten, K.; Borer,
B. C. Tetrahedron Lett. 2001, 42, 6481. (b) Kim, B. M.; Bae, S. J.; So, S. M.;
Yoo, H. T.; Chang, S. K.; Lee, J. H.; Kang, J. Org. Lett. 2001, 3, 2349.
(6) Ikunaka, M.; Matsumoto, J.; Fujima, Y.; Hirayama, Y. Org. Process
Res. Dev. 2002, 6, 49.
(7) (a) Inaba, T.; Yamada, Y.; Abe, H.; Sagawa, S.; Cho, H. J. Org. Chem.
2000, 65, 1623. (b) Zook, S. E.; Busse, J. K.; Borer, B. C. Tetrahedron Lett.
2000, 41, 7017.
Nelfinavir 1, a potent, orally active, effective inhibitor of
an HIV-protease, is one of the most prescribed therapeutic
agents to suppress the AIDS epidemic.1 It has attracted the
attention of synthetic chemists due to its huge market,
unique structural features comprising five stereogenic cen-
ters and a core four carbon backbone in which each carbon is
attached to a heteroatom.
(8) Ma, D.; Zou, B.; Zhu, W.; Xu, H. Tetrahedron Lett. 2002, 43, 8511.
(9) For the oxidative functionalization of disubstituted alkenes, see: (a)
Raghavan, S.; Rasheed, M. A.; Joseph, S. C.; Rajender, A. Chem Commun.
1999, 1845. (b) Raghavan, S.; Ramakrishna Reddy, S.; Tony, K. A.; Naveen
Kumar, Ch.; Varma, A. K.; Nangia, A. J. Org. Chem. 2002, 67, 5838. (c)
Raghavan, S.; Rajender, A.; Joseph, S. C.; Rasheed, M. A.; Ravi Kumar, K.
Tetrahedron: Asymmetry 2004, 15, 365. (d) For the oxidative functionaliza-
tion of tri-substituted alkenes, see: Raghavan, S.; Sreekanth, T. Tetrahedron
Lett. 2008, 49, 1169.
(10) For the addition of R-sulfinyl carbanions to imines derived from
nonenolizable aldehydes, see: (a) Tsuchihashi, G. I.; Iriuchijima, S.;
Maniwa, K. Tetrahedron Lett. 1973, 14, 3389. (b) Ronan, B.; Marchalin,
S.; Samuel, O.; Kagan, H. B. Tetrahedron Lett. 1988, 29, 6101. (c) Pyne, S. G.;
Boche, G. J. Org. Chem. 1989, 54, 2663. (d) Pyne, S. G.; Dikic, B. Chem.
Commun. 1989, 826. (e) Satoh, T.; Sato, T.; Oohara, T.; Yamakawa, K. J.
Org. Chem. 1989, 54, 3973. (f) Mahidol, C.; Reutrakul, V.; Prapansiri, V.;
Panyachotipun, C. Chem. Lett. 1984, 969.
(1) (a) Appelt, K.; Bacquet, R. J.; Bartlett, C. A.; Booth, C. L. J.; Freer,
S. T.; Fuhry, M. A. M.; Gehring, M. R.; Herrmann, S. M.; Howland, E. F.;
Janson, C. A.; Jones, T. R.; Kan, C. C.; Kathardekar, V.; Lewis, K. K.;
Marzoni, G. P.; Mathews, D. A.; Mohr, C.; Moomaw, E. W.; Morse, C. A.;
Oatley, S. J.; Ogden, R. C.; Reddy, M. R.; Reich, S. H.; Schoettlin, W. S.;
Smith, W. W.; Varney, M. D.; Villafranca, J. E.; Ward, R. W.; Webber, S.;
Webber, S. E.; Welsh, K. M.; White, J. J. Med. Chem. 1991, 34, 1925. (b)
Shetty, B. V.; Kosa, M. B.; Khalil, D. A.; Webber, S. Antimicrob. Agents
Chemother. 1996, 40, 110. (c) Kaldor, S. W.; Kalish, V. J.; Davies, J. F.;
Shetty, B. V.; Fritz, J. E.; Appelt, K.; Burgess, J. A.; Campanale, K. M.;
Chirgadze, N. Y.; Clawson, D. K.; Dressman, B. A.; Hatch, S. D.; Khalil, D.
A.; Kosa, M. B.; Lubbehusen, P. P.; Muesing, M. A.; Patick, A. K.; Reich,
S. H.; Su, K. S.; Tatlock, J. H. J. Med. Chem. 1997, 40, 3979.
(2) (a) Inaba, T.; Birchler, A. G.; Yamada, Y.; Sagawa, S.; Yokota, K.;
Ando, K.; Uchida, I. J. Org. Chem. 1998, 63, 7582. (b) The acid is available
commercially from the Aldrich Chemical Company, Inc.
(3) (a) Houpis, I. N.; Molina, A.; Reamer, R. A.; Lynch, J. E.; Volante, R.
P.; Reider, P. J. Tetrahedron Lett. 1993, 34, 2593. (b) Gohring, W.; Gokhale,
S.; Hilpert, H.; Roessler, F.; Schlageter, M.; Vogt, P. Chimia 1996, 50, 532. (c)
Available from the Aldrich Chemical Company, Inc.
(11) Pyne, S. G.; Dikic, B. J. Org. Chem. 1990, 55, 1932.
(12) (a) Raghavan, S.; Rajender, A. Tetrahedron Lett. 2004, 45, 1919. (b)
Raghavan, S.; Rajender, A. Tetrahedron 2004, 60, 5059.
(13) Ruano, J. L. G.; Alcudia, A.; Prado, M.; Barros, D.; Maestro, M. C.;
Fernandes, I. J. Org. Chem. 2000, 65, 2856.
498 J. Org. Chem. 2010, 75, 498–501
Published on Web 12/14/2009
DOI: 10.1021/jo902048t
r
2009 American Chemical Society

Raghavan et al.
JOCNote
SCHEME 1. Retrosynthetic Analysis
SCHEME 3. Stereoselectivity of Bromohydrin Formation from
anti-18
SCHEME 2. Probable Transition States
SCHEME 4. Stereoselectivity of Bromohydrin Formation from
syn-18
by reacting R-sulfinyl carbanions with chiral p-tolyl sulfinyli-
mine derived from benzaldehyde. Inspired by this report, we
began a model study14 on the reaction of the organolithium
reagent derived from methyl p-tolyl sulfoxide15 12 with sulfi-
nylimines 10 and 11 prepared16 from p-tolyl sulfinamide17 8and
t-butyl sulfinamide18 9, respectively. The major diastereomers
of 13-16 were assigned the depicted structure based on
precedent.13 The results collected in Table 1 (Supporting
Information) reveal that the reaction affords products in the
same ratio at different temperatures, though the yield was lower
while running the reaction at higher temperatures (compare
entries 1 and 2, entries 3 and 4, etc.). Also the stereoselectivity
was better using sulfinylimine 11 and sulfoxide (S)-12. It is clear
that the sulfinyl group on nitrogen has a large influence in
determining the stereochemistry of the newly created stereo-
genic center. Since t-butyl sulfinamide is readily prepared in a
large scale using asymmetric catalysis further reactions were
carried out using 9. The reaction of sulfinyl imine 11 with
(R)- and (S)-sulfoxide 12 probably proceeds through transition
states I and II to furnish the sulfinamides syn-14 and anti-16,
respectively, Scheme 2.
The sulfinamide anti-16 was deprotected using HCl/
dioxane,19 and the resulting amine hydrochloride anti-17
reacted with arenesulfonyl chlorides to furnish the sulfona-
mides anti-18a-c in a one-pot operation. The sulfonamides
were prepared to study the influence of steric and (or)
stereoelectronic effect of the aryl group on the stereo-
selectivity of bromohydrin formation. Thus, treatment of
sulfonamide anti-18a with N-bromosuccinimide (NBS)
in toluene in the presence of water and 2,6-lutidine afforded
a mixture of bromohydrins syn-19a and syn-20a in 90:10
ratio, respectively. Similarly, sulfonamide anti-18b afforded
bromohydrins syn-19b and syn-20b in 80:20 ratio. The
sulfonamide anti-18c reacted very stereoselectively to furnish
a single product, syn-19c, Scheme 3.
To explore further, the influence of the relative con-
figurations at carbon and sulfur on the stereoselectivity of
bromohydrin formation, sulfonamides syn-18a-c were pre-
pared from syn-14. Reaction of sulfonamides syn-18a and b
with NBS furnished bromohydrins anti-19a (dr 84:16) and
anti-19b (dr 78:22), while syn-18c yielded anti-19c as the sole
product,20 Scheme 4. It is apparent that the o-nosyl group was
better than the para-substituted sulfonamides.
A probable reason for the high stereoselectivity observed
with 18c is the minimization of steric interactions between
the π-complexed bromonium ion and the o-nitro substi-
tuent in the most stable conformation of 18c, Scheme 5. It
is generally agreed that the bromonium ion attacks the
π-faces of the alkene reversibly and the stereochemical
outcome of the neighboring group assisted reaction is
dependent on the relative energies of the diastereomeric
transition states. In the case of 18c, the o-nitro substituent
probably prevents the attack of the bromonium ion onto
the si-face of the alkene effectively than when the substi-
tuent is in the para-positions as in 18a and b leading to the
exclusive formation of 19c.
It is noteworthy that because the chirality of the sulfoxide
has a negligible effect (if at all) in the creation of both the
stereogenic centers, racemic aryl methyl sulfoxide can be
(14) Optically pure methyl p-tolyl sulfoxide was used in initial experi-
ments to standardize reaction conditions because it is more readily available
in excellent optical purity by a number of oxidation protocols.
(15) Drago, C.; Caggiano, L.; Jackson, R. F. W. Angew. Int., Ed. Eng.
2005, 44, 7221.
(16) (a) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli,
D. L.; Zhang, H. J. Org. Chem. 1999, 64, 1403. (b) Liu, G.; Cogan, D. A.;
Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 1278.
(17) Davis, F. A.; Reddy, R. E.; Szewczyk, J. M.; Reddy, G. V.;
Portonovo, P. S.; Zhang, H.; Fanelli, D.; Reddy, R. T.; Zhou, P.; Carroll,
P. J. J. Org. Chem. 1997, 62, 2555.
(20) The structure of anti-19c was confirmed by NOE studies on the
derived N,O-acetonide by reaction with 2,2-dimethoxypropane in the pre-
sence of cat CSA. The structure assigned to syn-19c was confirmed by
oxidation to a sulfone which was identical to that obtained from anti-19c.
(21) As pointed out in the text, though racemic methyl phenyl sulfoxide
could be used, we chose the (S)-sulfoxide for the ease of interpretation of
NMR spectra (single set of peaks). The sulfoxide was prepared following
Jackson’s protocol (ref 15) using the less expensive of the enantiomeric
ligands.
(18) Weix, D. J.; Ellman, J. A. Org. Lett. 2003, 5, 1317.
(19) Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 12.
J. Org. Chem. Vol. 75, No. 2, 2010 499

Raghavan et al.
JOCNote
SCHEME 5. Rationale for the Stereoselective Formation of 19c
SCHEME 7. Synthesis of Nelfinavir
SCHEME 6. Attempted Preparation of Epoxide 25
of amine 5 to the same pot furnished tertiary amine 32. The
N,O-acetal in 32 was deprotected27 using aq 4 N HCl in
dioxane to yield sulfonamide 33. The sulfonamide was
deprotected using mercapto ethanol28 to afford amine 3.
Acylation using acid chloride derived from 2 followed
by removal of the acetyl group as reported by Inaba and
co-workers yielded nelfinavir 1, Scheme 7. The physical
characteristics of synthetic 1 were in good agreement with
the data reported earlier.7a
In summary, we have designed a very highly stereoselec-
tive route to nelfinavir. The chirality of the t-butyl sulfinyl on
the imine nitrogen group was exploited to introduce the
nitrogen bearing stereocenter. By an appropriate choice of
a protecting group for the nitrogen atom, the bromohydrin
24 (19c) was prepared stereoselectively by 1,2-asymmetric
induction. Thus, in contrast to many earlier syntheses, we
have introduced both the stereogenic centers without re-
course to using chiral pool starting materials. We have
utilized the sulfoxide as an intramolecular nucleophile. It is
noteworthy that racemic methyl phenyl sulfoxide can be
employed because the N-sulfinyl group has an overriding
influence in the creation of the nitrogen bearing stereogenic
center. This methodology should be useful for preparing
other bioactives possessing the 1,2-amino alcohol subunit
used. Having found suitable conditions for the diastereo-
selective preparation of bromohydrin 19c, we began our
study using (S)-methyl phenyl sulfoxide21 21. Sulfinamide 22
(dr 98:2, HPLC) was converted to sulfonamide 23 as de-
scribed before. Reaction with NBS proceeded cleanly to
furnish bromohydrin 24, the structure of which was unam-
biguously provenbyX-raycrystallography.22 Elaboration of 1
from 24 required inversion of the carbinol stereocenter, intro-
duction of the perhydroisoquinoline subunit, and reduction of
the sulfoxide to sulfide. This conversion was envisioned by
subjecting epoxide 25 to acid-catalyzed 5-exo intramolecular
opening by the sulfinyl group23 and other transformations. In
the event, treatment of 24 with anhydrous potassium carbo-
nate in dry acetonitrile furnished none of the desired epoxide 25
but only a complex mixture of products.24 In an alternative
approach, we envisioned displacing the bromine in 24 by an
acetate, followed by converting the secondary hydroxy group
into its mesylate and forming an epoxide, thereby inverting the
carbinol configuration. In the event, treatment of 24 with
sodium acetate in anhydrous DMF led to the isolation of
variable amounts of azetidine 26 and unsaturated sulfoxide 27,
Scheme 6.
Exploring an alternate strategy, we decided to protect the
hydroxy group. Thus, treatment of 24 with an equivalent of
Mom-Cl in the presence of Hunig’s base afforded, instead of
the expected O-Mom ether, the N-Mom derivative 28.
Proceeding ahead,25 the bromine was replaced by treatment
with anhydrous sodium acetate in dry DMF to afford acetate
29, which was reduced26 to the sulfide 30 cleanly using TFAA
in the presence of NaI. Mesylation of the hydroxy group and
hydrolysis of the acetate in 31 using anhydrous potassium
carbonate in dry methanol furnished an epoxide (not
isolated) wherein the carbinol center was inverted. Addition
(25) Attempted intramolecular opening of the epoxide i obtained without
incident from bromohydrin 28 using Bi(OTf)3, CSA and aq 3 M H2SO4 in
dioxane furnished the diol ii as a result of nucleophilic attack at the distal
carbon. The structure of the diol was assigned by comparison with the diol
obtained by hydrolysis of acetate 29. Therefore, in all the above experiments,
only intermolecular attack takes place because sulfoxide configuration
should be inverted if intramolecular opening were taking place.
Also attempted inversion of the carbinol center of sulfide iii, obtained by
reduction of 28, using Mitsunobu protocol (p-nitrobenzoic acid, DEAD,
PPh3) returned only unreacted starting material.
(22) See Supporting Information.
(23) Westwell, A. D.; Thornton Pett, M.; Rayner, C. M. J. Chem. Soc.,
Perkin Trans. 1 1995, 847.
(24) The initially formed epoxide probably undergoes an aza-Payne
rearrangement followed by β-elimination of the resulting aziridine. Alter-
nately, an azetidine could be formed which then suffers β-elimination under
the basic conditions.
(26) Drabowicz, J.; Oae, S. Synthesis 1977, 6, 404.
(27) Miyata, O.; Ozawa, Y.; Ninomiya, I.; Naito, T. Tetrahedron 2000,
56, 6199.
(28) Miller, S. C.; Scanlan, T. S. J. Am. Chem. Soc. 1997, 119, 2301.
500 J. Org. Chem. Vol. 75, No. 2, 2010

Raghavan et al.
JOCNote
including HIV-protease inhibitors such as amprenavir and
saquinavir.
EtOAc (2 ꢀ 30 mL). The combined organic extracts were
successively washed with water (2 ꢀ 20 mL) and brine and dried
over Na2SO4. Evaporation of the solvent under reduced pres-
sure afforded a crude product which was purified by column
chromatography using 45% EtOAc/hexane (v/v) as the eluent to
Experimental Section
afford the acetate 29 (1.68 g, 3.36 mmol) in 84% yield as a
=
Sulfinamide 22. A round-bottom flask equipped with a
magnetic stir bar and nitrogen inlet was charged with anhy-
drous THF (130 mL) and cooled at 0 °C. Diisopropylamine
(33.6 mmol) was added followed by n-BuLi (2.5 M in hexane,
13.4 mL, 33.6 mmol) dropwise over 10 min. The reaction
mixture was stirred at this temperature for 20 min and then
cooled at -78 °C. A solution of (S)-methyl phenyl sulfoxide 21
(2.94 g, 21 mmol) in anhydrous THF (105 mL) was added
dropwise via a syringe to the above LDA solution and the
mixture stirred for 30 min at the same temperature. To a stirred
solution of sulfinylimine 11 (3.34 g, 21 mmol) in anhydrous THF
(150 mL) cooled at -78 °C was added the solution of the sulfinyl
carbanion generated above, via a cannula, and the reaction was
quenched immediately by the addition of aqueous saturated
NH4Cl solution. The two layers were separated, the aqueous layer
was extracted with ethyl acetate, and the combined organic layers
were washed with brine and dried over Na2SO4. The solvent was
evaporated under reduced pressure to afford a crude product,
which was purified by column chromatography using 10%
EtOAc/CHCl3 (v/v) as the eluent to afford the sulfinamide 22
(5.89 g, 19.7 mmol) in 94% yield. Gummy liquid. TLC: Rf 0.2
(60% EtOAc/hexane). [R]D25 = -121 (c 1.2, CHCl3). IR (neat):
3201, 2958, 1632, 1469, 1390, 1171, 1043, 751 cm-1. 1H NMR (300
MHz, CDCl3): δ 7.69 (m, 2H), 7.58-7.48 (m, 3H), 6.07-5.96 (m,
1H), 5.36 (d, J = 16.6 Hz, 1H), 5.27 (d, J = 10.5 Hz, 1H),
4.46-4.36 (m, 1H), 4.28 (d, J = 8.3 Hz, NH), 3.08-2.96 (m, 2H),
1.29 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 143.1, 137.1, 130.6,
128.8, 123.3, 116.8, 63.2, 56.3, 54.5, 22.3. MS (ESI): 322 [M þ
Na]þ. HRMS (ESI): m/z [M þ Na]þ calcd for C14H21NO2NaS2:
322.0911. Found: 322.0908.
Bromohydrin 24. To a stirred mixture of sulfonamide 23
(5.28 g, 13.9 mmol) and 2,6-lutidine (3.2 mL, 27.8 mmol) in
toluene (70 mL) was added water (0.5 mL, 27.8 mmol) followed
by freshly recrystallized N-bromosuccinimide (4.9 g, 27.8 mmol).
The reaction mixture was stirred at room temperature until TLC
examination revealed complete conversion of starting material.
The reaction was quenched by adding aqueous saturated
NaHCO3 solution. The two layers were separated and the
aqueous layer was extracted with EtOAc. The combined organic
layers were successively washed with water, brine, and dried
over Na2SO4. Evaporation of the solvent afforded a crude
product, which was purified by column chromatography using
10% EtOAc/CHCl3 (v/v) as the eluent to furnish the bromo-
25
gummy liquid. TLC: Rf 0.3 (65% EtOAc/hexane). [R]D
þ204 (c 1.3, CHCl3). IR (neat): 3408, 2960, 1739, 1544, 1442,
1364, 1231, 1171, 1046, 748 cm-1. 1H NMR (400 MHz, CDCl3):
δ 8.14-8.11 (m, 1H), 7.82-7.76 (m, 2H), 7.68-7.65 (m, 1H),
7.52-7.47 (m, 3H), 7.41-7.39 (m, 2H), 5.03 (d, J = 11.8 Hz,
1H), 4.71 (d, J = 11.8 Hz, 1H), 4.34 (td, J = 3.4 and 10.1 Hz,
1H), 4.28 (dd, J = 7.6 and 11.8 Hz, 1H), 4.19-4.11 (m, 1H), 4.05
(dd, J = 4.2 and 11.8 Hz, 1H), 3.91 (d, J = 9.3 Hz, OH), 3.49 (s,
3H), 3.47 (dd, J = 10.1 and 13.5 Hz, 1H), 2.55 (dd, J = 2.5 and
13.5 Hz, 1H), 2.08 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ 170.7, 147.7, 142.7, 134.3, 132.9, 132.2, 131.5, 131.3, 129.41
124.3, 123.6, 77.7, 69.2, 65.0, 56.6, 56.1, 54.0, 20.7. MS (ESI):
523 [M þ Na]þ. HRMS (ESI): m/z [M þ Na]þ calcd for C20H24-
N2O9NaS2: 523.0820. Found: 523.0835.
Compound 32. In a 25 mL round-bottom flask equipped with
a magnetic stir bar were placed mesylate 31 (1.44 g, 2.56 mmol)
and anhydrous K2CO3 (353 mg, 2.56 mmol) in dry MeOH
(10 mL). The resulting mixture was stirred for 3 h when TLC
examination revealed complete conversion of starting material.
Amine 5 (691 mg, 2.9 mmol) was added in one portion and then
stirred further until no remaining starting material could be
detected by TLC (ca. 8 h). Ether (12 mL) was added to the
reaction mixture and the precipitated solids were filtered
through a pad of Celite. The filtrate was evaporated in vacuo
to afford a crude product which was purified by column
chromatography using 20% EtOAc/hexane (v/v) as the eluent
to afford tertiary amine 32 (1.5 g, 2.28 mmol) in 89% yield as a
colorless solid. Mp: 86-87 °C. TLC: Rf 0.3 (35% EtOAc/
25
hexane). [R]D = þ6 (c 1.1, CHCl3). IR (neat): 3401, 2925,
2861, 1673, 1544, 1455, 1364, 1171, 1031, 757 cm-1. 1H NMR
(500 MHz, CDCl3): δ 8.00 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 7.8
Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H),
7.16-7.13 (m, 2H), 7.09-7.06 (m, 3H), 5.94 (s, NH), 5.12 (d,
J = 12.7 Hz, 1H), 4.70 (d, J = 12.7 Hz, 1H), 4.29-4.23 (m, 2H),
3.51 (s, 3H), 3.34 (dd, J = 3.9 and 13.7 Hz, 1H), 3.22 (dd, J = 2.9
and 11.7 Hz, 1H), 3.13 (dd, J = 11.7 and 13.7 Hz, 1H), 2.59 (dd,
J = 8.8 and 12.7 Hz, 1H), 2.50 (dd, J = 2.9 and 11.7 Hz, 1H),
2.24 (dd, J = 5.8 and 12.7 Hz, 1H), 2.14 (dd, J = 3.9 and 11.7
Hz, 1H), 2.05-1.90 (m, 2H), 1.82-1.76 (m, 2H), 1.71-1.63 (m,
2H), 1.57-1.53 (m, 2H), 1.51-1.41 (m, 2H), 1.28 (s, 9H),
1.27-1.24 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 173.3,
147.5, 135.9, 133.8, 132.6, 131.7, 131.6, 128.7, 127.6, 125.5,
124.3, 76.0, 71.9, 71.0, 58.9, 58.72, 58.7, 56.2, 50.7, 35.6, 33.3,
30.8, 30.4, 28.5, 27.3, 26.3, 25.9, 20.5. MS (ESI): 663 [M þ H]þ.
HRMS (ESI): m/z [M þ H]þ calcd for C32H47N4O7S2: 663.2886.
Found: 663.2909.
hydrin 24 (5.1 g, 10.7 mmol) in 77% yield as a colorless solid.
Mp: 169-170 °C. TLC: Rf 0.3 (20% EtOAc/CHCl3). [R]D
25
=
þ49 (c 0.5, CHCl3). IR (neat): 3353, 3212, 2925, 1706, 1542,
1
1462, 1365, 1172, 1054, 1004, 752 cm-1. H NMR (300 MHz,
CDCl3): δ 8.10-8.07 (m, 1H), 7.90-7.87 (m, 1H), 7.80-7.71 (m,
2H), 7.64-7.59 (m, 2H), 7.57-7.54 (m, 3H), 6.37 (d, J = 6.8 Hz,
NH), 4.92 (d, J = 3.7 Hz, OH), 4.31-4.26 (m, 1H), 4.20-4.12
(m, 1H), 3.42 (dd, J = 6.8 and 13.6 Hz, 1H), 3.31 (dd, J =
5.2 and 10.5 Hz, 1H), 3.01-2.95 (m, 2H). 13C NMR (75 MHz,
CDCl3): δ 147.8, 141.5, 134.0, 133.5, 132.9, 131.6, 131.0, 129.6,
125.4, 124.2, 71.8, 62.7, 52.3, 32.2. MS (ESI): 499 [M þ Na]þ.
HRMS (ESI): m/z [M þ Na]þ calcd for C16H17N2O6NaS2Br:
498.9609. Found: 498.9607.
Compound 29. In a 50 mL round-bottom flask equipped with
a magnetic stir bar were placed MOM-ether 28 (2.1 g, 4 mmol)
and NaOAc (2.62 g, 32 mmol) in anhydrous DMF (20 mL). The
resulting mixture was stirred at 90 °C until no remaining starting
material could be detected by TLC (ca. 8 h). The reaction
mixture was allowed to cool to room temperature, water
(20 mL) was added, and then the mixture was extracted with
Acknowledgment. S.R. is thankful to Dr. J. M. Rao,
Head, Org. Div. I, and Dr. J. S. Yadav, Director, IICT, for
constant support and encouragement. V.K is thankful to
CSIR, New Delhi for a fellowship. Financial assistance from
DST (New Delhi) is gratefully acknowledged.
Supporting Information Available: Experimental procedures
and physical data for compounds 10, 11, syn-13, syn-14, anti-15,
anti-16, anti-18a, anti-18b, anti-18c, syn-18a, syn-18b, syn-18c,
syn-19a,syn-19b,syn-19c,anti-19a,anti-19b,anti-19c,N,O-acetonide
from anti-19c, sulfone from syn-19c, 23, 28, 30, 31, 33, 3, 1, i, ii, iii,
Table 1, copies of spectra for all new compounds, cif data, and
X-ray structure of 24. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 2, 2010 501