A short synthesis of the HIV-protease inhibitor nelfinavir via a diastereoselective addition of ammonia to the α,β-unsaturated sulfoxide derived from (R)-glyceraldehyde acetonide

Article abstract of DOI:10.1016/S0040-4039(02)02077-4

Diastereoselective Michael addition of ammonia to sulfoxide 3a derived from (R)-glyceraldehyde acetonide provides amine 4a, which is converted into Nelfinavir using BF₃·Et₂O/NaI reduction and subsequent coupling reactions as key steps.

Full text of DOI:10.1016/S0040-4039(02)02077-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8511–8513
A short synthesis of the HIV-protease inhibitor nelfinavir via a
diastereoselective addition of ammonia to the a,b-unsaturated
sulfoxide derived from (R)-glyceraldehyde acetonide
Dawei Ma,* Bin Zou, Wei Zhu and Huadong Xu
State Key Laboratory of Bio-organic and Natural Product Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received 23 July 2002; revised 2 September 2002; accepted 20 September 2002
Abstract—Diastereoselective Michael addition of ammonia to sulfoxide 3a derived from (R)-glyceraldehyde acetonide provides
amine 4a, which is converted into Nelfinavir using BF3·Et2O/NaI reduction and subsequent coupling reactions as key steps.
© 2002 Elsevier Science Ltd. All rights reserved.
Nelfinavir mesylate is one of the most potent HIV-
protease inhibitors and received FDA approval in March
1997 for treatment of HIV infection.1 The marketing
need and structural complexity have attracted much
attention towards its total synthesis.2–10 To date, several
concise protocols have been disclosed.2–8 Most of these
relied on using either (5R,6S)-2,2-dimethyl-5-hydroxy-
1,3-dioxepan-6-ylammonium acetate 15–7 or the epoxide
of sulfoxide or sulfone B. Although there is no report
regarding the addition of an amine to olefin 3, the
diastereoselective Michael addition11 of benzylamine or
other amines to a,b-unsaturated esters derived from
(R)-glyceraldehyde acetonide gave us encouragement
that we might be able to prepare B from 3 in a
diastereoselective manner.
28 derived from N-benzyloxycarbonyl-S-phenyl-
L
-cys-
Accordingly, we prepared the olefins 3a and 3b by the
following methods: (1) trapping the lithium salt gener-
ated from methyl phenyl sulfoxide with (R)-glyceralde-
hyde acetonide afforded the corresponding alcohol,
which was subjected to mesylation/elimination to
provide 3a;12 (2) phosphorylation of methyl phenyl
sulfone and subsequent Wittig–Horner reaction with
teine as an intermediate. The poor diastereoselectivity in
obtaining 1 and requirement for many steps to reach 2
prompted us to explore an alternative route.
As shown in Scheme 1, we chose compound A as our
intermediate, which could be assembled by the reduction
Scheme 1.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02077-4

8512
D. Ma et al. / Tetrahedron Letters 43 (2002) 8511–8513
(R)-glyceraldehyde acetonide gave 3b (Scheme 2).13 The
Michael addition of amines to 3a or 3b was studied
subsequently and the results are summarized in Table 1.
sulfide, the attempt to convert 4b to 4a through deben-
zylation via either hydrogenolysis catalyzed by Pd/C or
using Na/NH3 reductive cleavage also failed. Thus, we
had to use 4a, which was produced by addition of
ammonia to 3a, to progress further (Scheme 4).
As indicated in Table 1, in the case of benzylamine as
a nucleophilic agent, both the sulfoxide 3a and the
sulfone 3b provided the desired addition products in
good yield and diastereoselectivity (entries 1 and 9).
However, when ammonia was utilized as a nucleophilic
agent, the reaction worked but with lower diastereose-
lectivity (compare entries 1 and 2). Attempts to over-
come this drawback by varying reaction solvents or
introducing an additive11e failed (entries 3 and 4) or
caused slight improvement (entries 5 and 6). In addi-
tion, either lowering or raising the reaction temperature
resulted in a decrease in diastereoselectivity (compare
entries 6–8). The reason for this dramatic change was
not clear.
Reduction of the diastereomeric mixture of 4a and 5a
(Table 1, entries 2 or 6) with BF3·Et2O/NaI delivered
sulfide 8 as a diastereomeric mixture in 71% yield.17
This conversion was also done by Raney–Nickel cata-
lyzed hydrogenation at room temperature. In this case
the yield was slightly higher (80%) than BF3·Et2O/NaI
reduction but the reaction time was much longer (1
week). Coupling 8 with 3-acetoxy-2-methylbenzoic acid
mediated by EDCI/HOBt provided separable 9 (72%
yield) and its 2-epimer (17% yield). The overall yield
from 3a to 9 was about 40%. Next, hydrolysis of the
acetonide moiety of 9 was carried out in 1N HCl/
CH3OH (1:10) at 40°C for 3 h to afford diol 10.
Treatment of this diol with tosyl chloride followed by
coupling with the amine 11 furnished Nelfinavir in 59%
yield.
Because both 4b and 4c were obtained in a highly
diastereoselective manner, we first used them to attempt
the further transformations. Thus, Pd/C catalyzed
hydrogenation of 4c provided debenzylated product 6
in 89% yield (Scheme 3). However, the subsequent
reduction of the sulfone 6 to the sulfide 7 failed using
several reducing reagents such as LAH,14 DIBAL-H,15
and LAH/TiCl4.16 Although later we found a suitable
method to reduce the sulfoxide to the corresponding
In conclusion, we have developed a short and efficient
synthesis of Nelfinavir utilizing a novel chiral C4 build-
ing block B derived from (R)-glyceraldehyde acetonide.
Further reaction condition optimization to improve the
yields and selectivity in some steps is in hand.
Scheme 2.
Table 1. The Michael addition of amines to olefins 3a
Entry
Substrate
Reaction conditions
Yield (%)b
Ratio (4/5)c
1
2
3
4
5
6
7
8
9
3a
3a
3a
3a
3a
3a
3a
3a
3b
BnNH2/MeOH, reflux, 5 h
NH3/MeOH, 60°C, 18 h
NH3/EtOH, 60°C, 24 h
NH3/MeCN, 60°C, 24 h
NH3/MeOH, 10 equiv. LiCl, 60°C, 24 h
NH3/1/1 MeOH/MeCN, 60°C, 24 h
NH3/1/1 MeOH/MeCN, 30°C, 4 days
NH3/1/1 MeOH/MeCN, 100°C, 5 h
BnNH2/MeOH, reflux, 5 h
85
81
68
11/1
4/1
3.4/1
–
4.7/1
4.7/1
3.2/1
3/1
d
–
78
71
62
80
78
19/1
a Reaction conditions: 3 (0.5 mmol), BnNH2 (10 mmol) or saturated NH3 in indicated solvent.
b Isolated yield.
c Determined by HPLC.
d No reaction occurred.

D. Ma et al. / Tetrahedron Letters 43 (2002) 8511–8513
8513
Scheme 3.
Scheme 4.
Acknowledgements
M.; Chirgadze, N. Y.; Clawson, D. K.; Dressman, B. A.;
Hatch, S. D.; Khalil, D. A.; Kosa, M. B.; Lubbehusen, P.
P.; Tatlock, J. H. J. Med. Chem. 1997, 40, 3979–3985.
9. Kim, B. M.; Bae, S. J.; So, S. M.; Yoo, H. T.; Chang, S.
K.; Lee, J. H.; Kang, J. Org. Lett. 2001, 3, 2349–2351.
10. Herradura, P. S.; Pendola, K. A.; Guy, R. K. Org. Lett.
2000, 2, 2019–2022.
The authors are grateful to the Chinese Academy of
Sciences, National Natural Science Foundation of
China (grant 20132030), and Qiu Shi Science and Tech-
nologies Foundation for their financial support.
11. (a) Matsunaga, H.; Sakamaki, T.; Nagaoka, H.; Yamada,
Y. Tetrahedron Lett. 1983, 24, 3009–3012; (b) Lima, P.
G.; Sequeira, L. C.; Costa, P. R. R. Tetrahedron Lett.
2001, 42, 3525–3527; (c) Pinto, A. C.; Abdala, R. V.;
Costa, P. R. R. Tetrahedron: Asymmetry 2000, 11, 4239–
4243; (d) Sewald, N.; Hiller, K. D.; Korner, M.; Find-
eisen, M. J. Org. Chem. 1998, 63, 7263–7274; (e) Horni,
A.; Linden, A.; Hesse, M. Helv. Chim. Acta 1998, 81,
1303–1318.
12. Hohmann, M.; Krause, N. Chem. Ber. 1995, 128, 851–
860.
13. Lee, J. W.; Oh, D. Y. Synth. Commun. 1989, 19, 2209–
2212.
14. (a) Taylor, E. C.; Palmer, D. C.; George, T. J.; Fletcher,
S. R.; Tseng, C. P.; Harrington, P. J. J. Org. Chem. 1983,
48, 4852–4860; (b) Lena, L. J.; Escaller, U. C. Anal.
Chem. 1982, 54, 688–691.
15. Ager, D. J. J. Chem. Soc. Perkin Trans. 1 1986, 63,
195–204.
16. Akgun, E.; Mahmood, H.; Mathis, C. A. J. Chem. Soc.
Chem. Commun. 1994, 6, 761–762.
17. Vankar, Y. D. Tetrahedron Lett. 1985, 26, 2717–2720.
References
1. For a review, see Rabasseda, X.; Martel, A. M.; Cas-
taner, J. Drugs Fut. 1997, 22, 371–375.
2. For a review, see Ghosh, A. K.; Bilcer, G.; Schilitz, G.
Synthesis 2001, 2203–2229.
3. 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, 6481–6484.
4. Rieger, D. L. J. Org. Chem. 1997, 62, 8546–8548.
5. Inaba, T.; Birchler, A. G.; Yamada, Y.; Sagawa, S.;
Yokota, K.; Ando, K.; Uchida, I. J. Org. Chem. 1998, 63,
7582–7583.
6. Inaba, T.; Yamada, Y.; Abe, H.; Sagawa, S.; Cho, H. J.
Org. Chem. 2000, 65, 1623–1628.
7. Zook, S. E.; Busse, J. K.; Borer, B. C. Tetrahedron Lett.
2000, 41, 7017–7020.
8. Kaldor, S. W.; Kalish, V. J.; Davies, J. F.; Shetty, B. V.;
Fritz, J. E.; Appelt, K.; Burgess, J. A.; Campanale, K.