Formal total synthesis of borrelidin: synthesis of C1-C11 fragment via desymmetrization strategy

Article abstract of DOI:10.1016/j.tetlet.2009.03.196

A stereoselective formal total synthesis of borrelidin is described. The synthetic strategy for synthesis of C1-C11 fragment features desymmetrization of Diels-Alder adduct, Sharpless asymmetric epoxidation, regioselective opening of chiral epoxide, and a

Full text of DOI:10.1016/j.tetlet.2009.03.196

Tetrahedron Letters 50 (2009) 3772–3775
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Formal total synthesis of borrelidin: synthesis of C1–C11 fragment via
desymmetrization strategy
*
J. S. Yadav , Padmavani Bezawada, Venugopal Chenna
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereoselective formal total synthesis of borrelidin is described. The synthetic strategy for synthesis of
C1–C11 fragment features desymmetrization of Diels–Alder adduct, Sharpless asymmetric epoxidation,
regioselective opening of chiral epoxide, and alkylation using Evans chiral auxiliary.
Ó 2009 Published by Elsevier Ltd.
Received 6 March 2009
Revised 26 March 2009
Accepted 30 March 2009
Available online 2 April 2009
Keywords:
Borrelidin, Desymmetrization
Sharpless asymmetric epoxidation
Evan’s chiral auxiliary
Borrelidin (1), a structurally unique 18-membered macrolide
antibiotic possessing anti-Borrelia activity was first isolated from
Streptomyces rochei in 1949 by Berger et al.1 First planar structure
was proposed by Keller-Schierlein in 1967,2 and X-ray crystallo-
graphic studies by Anderson et al. revealed its absolute structure.3
It has reduced polypropionate moiety with four methyl groups
possessing a distinctive syn/syn/anti relationship, a Z/E cyanodiene
unit at C12–C15, and a cyclopentane carboxylic acid subunit at
C17. Borrelidin possesses antiviral,4 antibacterial activity,1,5 in
addition to anti-angiogenesis effects6 and is found to display inhib-
itory activity toward cyclin-dependent kinase Cdc28/Cln2 of Sac-
charomyces cerevisiae.7 Interesting biological activity and complex
structural feature of borrelidin attracted many synthetic chemists
which resulted in first total synthesis by Morken and co-workers,8
followed by efforts from various other groups for the total synthe-
sis through synthetic9–11 and biosynthetic pathways.12
and stereoselective Evans alkylation. Compound 6 is obtained by
stereoselective opening of epoxide 7, which in turn could be ob-
tained from compound 8. Compound 8 is accessible from the
known precursor 9 (Scheme 1).
Our synthesis started with the precursor 9, which was prepared
earlier in our group and utilized to make several natural prod-
ucts.15 Compound 9 was hydroformylated, further protected as
methanesulfonate, and treated with DBU to get olefin 10.16 The
olefin 10 was stereoselectively reduced to obtain compound 11,
which on further reductive ring opening with DIBAL-H yielded
compound 12. Protection of 1,3-diol as acetonide and deprotection
of benzyl group provided compound 13, which was selectively pro-
tected as monobenzyl ether and the secondary hydroxyl group was
converted into the xanthate ester and reduced to obtain compound
14. Deprotection of acetonide and selective primary hydroxyl pro-
tection with TBDPS–Cl yielded compound 8 (Scheme 2).
Our ongoing research on the synthesis of biologically active
molecules by desymmetrization strategy, and the fascinating bio-
logical activity of borrelidin encouraged us to select this molecule
as a target for total synthesis. We herein report the synthesis of
C1–C11 fragment of borrelidin 1.
The retrosynthetic plan for the borrelidin 1 was similar to the
Satoshi Omura’s approach10 in which borrelidin 1 could be easily
obtained from the carboxylic acid compound 3 and the alcohol 4.
Compound 3 would be synthesized from compound 5 by simple
reduction and oxidation reactions, which in turn could be obtained
from compound 6 by extending two carbons using Wittig reaction
Compound 8 was converted to xanthate ester, further reduced
to provide compound 15, which was subjected to debenzylation
followed by oxidation and further extension of two carbon units
by a C2 Wittig reaction yielded compound 16. The ester was re-
duced to alcohol and subjected to Sharpless asymmetric epoxida-
tion13 to obtain compound 7. Protection of hydroxyl group
followed by reductive opening of epoxide afforded compound 17.
The resulting hydroxyl group was protected with TBDMS–Cl and
TBDPS group was selectively deprotected using NH4F and MeOH17
to afford compound 6 (Scheme 3).
Compound 6 was oxidized to aldehyde, and subjected to Wittig
reaction to obtain compound 18. The resulting olefin was selec-
18
tively hydrogenated using NiCl4 and NaBH4 and then the ester
* Corresponding author. Tel.: +91 40 27193030; fax: +91 40 27160512.
E-mail address: yadavpub@iict.res.in (J.S. Yadav).
was hydrolyzed in basic conditions to yield compound 19. The acid
0040-4039/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.03.196

J. S. Yadav et al. / Tetrahedron Letters 50 (2009) 3772–3775
3773
OH
HO
NC
O
O
H
CO2H
Borrelidin (1)
OTBS
CO2H
OTBS
O
OTHP
3
OHC
Br
+
O
1
OH
Br
H
NC
OPMB
H
NC
OPMB
2
4
Ph
HO
OBn
O
3
N
OBn
OTBS
6
O
O
OTBS
5
O
O
OH
BnO
OTBDPS
O
TBDPSO
O
8
7
OH
9
OBn
Scheme 1. Retrosynthetic analysis.
O
O
O
O
e
a, b, c
d
O
O
O
O
O
OBn
OBn
OBn
10
11
9
HO
HO
OH
h, i, j
BnO
f, g
OH
13
O
O
OBn OH
O
O
14
12
k, l
OTBDPS
BnO
OH
8
Scheme 2. Reagents and conditions: (a) LDA, paraformaldehyde, THF, ꢀ78 °C; (b) MsCl, Et3N, DCM, 0 °C–rt; (c) DBU, DCM, rt, 60% (three steps); (d) H2, 10%, Pd–C, Na2CO3,
EtOAc, rt, 95%; (e) DIBAL-H, DCM, rt, 85%; (f) 2,2-DMP, acetone, PTSA, rt; (g) Li, Naphthalene, ꢀ23 °C, 65% (two steps); (h) NaH, BnBr, THF, 0 °C; (i) NaH, CS2, MeI, THF; (j)
Bu3SnH, cat. AIBN, toluene, reflux, 77% (three steps); (k) cat. PTSA, MeOH; (l) TBDPS–Cl, imidazole, DCM, rt, 79% (two steps).
c, d, e
a, b
OTBDPS
BnO
8
15
O
h, i
f, g
j, k
TBDPSO
TBDPSO
OEt
TBDPSO
OH
16
O
7
OBn
HO
OBn
OH
6
17
OTBS
Scheme 3. Reagents and conditions: (a) NaH, CS2, MeI, THF; (b) Bu3SnH, cat. AIBN, toluene, reflux, 83% (two steps); (c) Li, Naphthalene, ꢀ23 °C; (d) IBX, DMSO, THF, rt; (e)
Ph3P@CHCOOEt, benzene, rt, 80% (three steps); (f) DIBAL-H, DCM, rt; (g) (ꢀ)-DIPT, TBHP, titanium isopropoxide, DCM, 80% (two steps); (h) Red-Al, THF, 0 °C; (i) NaH, BnBr,
THF, 0 °C, 73% (two steps); (j) TBSOTf, 2,6-lutidine, DCM, 0 °C; (k) NH4F, MeOH, rt, 78% (two steps).

3774
J. S. Yadav et al. / Tetrahedron Letters 50 (2009) 3772–3775
c, d
a, b
EtO
OBn
6
O
18
Ph
OTBS
HO
OBn
O
e, f
g, h
N
OBn
O
OTBS
O
19
O
5
OTBS
i, j
THPO
OBn
THPO
OH
OTBS
O
OTBS
3
20
Scheme 4. Reagents and conditions: (a) IBX, DMSO, THF, rt; (b) Ph3P@CHCOOEt, benzene, rt, 95% (two steps); (c) NaBH4, NiCl4, MeOH; (d) LiOH, MeOH, H2O, THF (1:1:1), 0 °C
78% (two steps); (e) Et3N, Piv-Cl, THF, then (S)-4-benzyl-2-oxazolidinone, LiCl; (f) NaHMDS, MeI, THF, ꢀ78 °C, 59% (two steps); (g) NaBH4, MeOH; (h) 3,4-dihydropyran, cat.
PTSA, DCM, 72% (two steps); (i) Li, naphthalene, THF, ꢀ23 °C; (j) BAIB, TEMPO, acetone, water (8:2), 55% (two steps).
15. (a) Yadav, J. S.; Rao, C. S.; Chandrasekhar, S.; Ramarao, A. V. Tetrahedron Lett. 1995,
group was activated by forming mixed anhydride, coupled to Evans
36, 7717–7720; (b) Yadav, J. S.; Abraham, S.; Reddy, M. M.; Sabitha, G.; Sankar, A.
R.; Kunwar, A. C. Tetrahedron Lett. 2001, 42, 4713–4716; (c) Yadav, J. S.; Abraham,
S.; Reddy, M. M.; Sabitha, G.; Sankar, A. R.; Kunwar, A. C. Tetrahedron Lett. 2002,
chiral oxazolidinone and stereoselectively methylated to obtain
compound 5.14 Compound 5 was reduced to alcohol and was pro-
43, 3453; (d) Yadav, J. S.; Md. Ahmed, M. Tetrahedron Lett. 2002, 43, 7147–7150;
(e) Yadav, J. S.; Reddy, K. B.; Sabitha, G. Tetrahedron Lett. 2004, 45, 6475–6476; (f)
Yadav, J. S.; Srinivas, R.; Sathiah, K. Tetrahedron Lett. 2006, 47, 1603–1606; (g)
Yadav, J. S.; Venkatram Reddy, P.; Chandraiah, L. Tetrahedron Lett. 2007, 48, 145–
tected as THP ether to provide compound 20. Li-Naphthalene med-
iated deprotection of benzyl group yielded free alcohol, which was
smoothly oxidized by using TEMPO, BAIB19 to obtain the final com-
148; (h) Yadav, J. S.; Pratap, T. V.; Rajender, V. J. Org. Chem. 2007, 72, 5882–5885;
(i) Yadav, J. S.;Ravindar, K.;Reddy, B. V. S. Synlett2007, 1957–1959;(j)Yadav, J. S.;
Venugopal, C. Synlett 2007, 2262–2266.
pound 3. Analytical data were compared and found to be identical
with those of the reported compound10 (Scheme 4). All the impor-
20–26
tant compounds were characterized by their spectral data.
16. Majetich, G.; Song, J.; Leigh, A. J.; Condon, S. M. J. Org. Chem. 1993, 58, 1030–
1037.
In conclusion we have completed the synthesis of C1–C11 frag-
ment of borrelidin, all the stereogenic centers were obtained
through desymmetrization strategy, Sharpless asymmetric epoxi-
dation, regioselective opening of chiral epoxide and stereoselective
alkylation using Evan’s chiral auxiliary.
17. Zhang, W.; Robins, M. J. Tetrahedron Lett. 1992, 33, 1177–1180.
18. Satoh, T.; Nanba, K.; Suzuki, S. Chem. Pharm. Bull. 1971, 19, 817.
19. (a) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org.
Chem. 1997, 62, 6974–6977; (b) Epp, J. B.; Widlanski, T. S. J. Org. Chem. 1999, 64,
293–295.
20. Analytical data for compound 11: Colorless oil; ½a D25
ꢁ
ꢀ78.44 (c 0.5, CHCl3). IR
(KBr): 2926, 1742, 1452, 1387, 1200, 1069, 970 cmꢀ1
.
1H NMR (300 MHz,
CDCl3): d 7.38-7.21 (m, 5H), 5.37 (d, J = 2.3 Hz, 1H), 4.75 (d, J = 11.4 Hz, 1H),
4.47 (d, J = 11.4 Hz, 1H), 4.03 (dd, J = 4.4, 6.5 Hz, 1H), 3.62-3.58 (m, 1H), 3.04 (q,
J = 7.2, 14.5 Hz, 1H), 2.40-2.29 (m, 1H), 2.07-1.96 (m, 1H), 1.19 (d, J = 6.9 Hz,
3H), 1.16 (d, J = 6.7 Hz, 3H), 1.04 (d, J = 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3): d
170.9, 137.9, 128.6, 128.5, 128.0, 100.9, 80.0, 77.8, 74.8, 41.6, 41.0, 40.3, 15.3,
13.6, 12.6. MS (ESI): m/z 313.1 (M+Na)+. HRMS (ESI): calcd for C17H22O4Na:
313.1415. Found: 313.1411.
Acknowledgment
B.P.V. and C.V. thank CSIR, New Delhi for research fellowships.
References and notes
21. Analytical data for compound 8: Viscous liquid; ½a D25
ꢁ
+10.8 (c 1.9, CHCl3). IR
(KBr): 3452, 2957, 2926, 2856, 1639, 1458, 1427, 1368, 1107, 1022, 701 cmꢀ1
.
1. Berger, J.; Jampolsky, L. M.; Goldberg, M. W. Arch. Biochem. 1949, 22, 476.
2. Keller-Schierlein, W. Helv. Chim. Acta 1967, 50, 731.
3. Anderson, B. F.; Herlt, A. J.; Rickards, R. W.; Robertson, G. B. Aust. J. Chem. 1989,
42, 717.
4. Dickinson, L.; Griffiths, A. J.; Mason, C. G.; Mills, R. F. Nature 1965, 206, 265.
5. Singh, S. K.; Gurusiddaiah, S.; Whalen, J. W. Antimicrob. Agents Chemother. 1985,
27, 239.
6. Wakabayashi, T.; Kageyama, R.; Naruse, N.; Tsukahara, N.; Funahashi, Y.; Kitoh,
K.; Watanabe, Y. J. Antibiot. 1997, 50, 671.
7. Tsuchiya, E.; Yukawa, M.; Miyakawa, T.; Kimura, K.; Takahashi, H. J. Antibiot.
2001, 54, 84.
8. Duffey, M. O.; LeTiran, A.; Morken, J. P. J. Am. Chem. Soc. 2003, 125, 1458–1459.
and references cited therein.
9. Hanessian, S.; Yang, Y.; Giroux, S.; Mascitti, V.; Ma, J.; Raeppel, F. J. Am. Chem.
Soc. 2003, 125, 13784–13792. and references cited therein.
10. (a) Nagamitsu, T.; Takano, D.; Marumoto, k.; Fukuda, T.; Furuya, K.; Otoguro, K.;
Takeda, K.; Kuwajima, I.; Harigaya, Y.; Omura, S. J. Org. Chem. 2007, 72, 2744–2756;
(b) Nagamitsu, T.; Takano, D.; Fukuda, T.; Otoguro, K.; Kuwajima, I.; Harigaya, Y.;
Omura, S. Org. Lett. 2004, 11, 1865–1867. and references cited therein.
11. Vong, B. G.; Kim, S. H.; Abraham, S.; Theodorakis, E. A. Angew. Chem., Int. Ed.
2004, 43, 3947–3951. and references cited therein.
12. Olano, C.; Wilkinson, B.; Sanchez, C.; Moss, S. J.; Sheridan, R.; Math, V.; Weston,
A. J.; Brana, A. F.; Martin, C. J.; Oliynyk, M.; Mendez, C.; Leadlay, P. F.; Salas, J. A.
Chem. Biol. 2004, 11, 87–97.
13. (a) Finn, M. G.; Sharpless, K. B.. In Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic Press: New York, 1985; Vol. 5, Chapter 8,. p 247 (b) Rossiter, B. E.. In
Asymmetric Synthesis; Morrison, J. D., Ed.; Academic press: New York, 1985;
Vol. 5, Chapter 7,. p 193 (c) Pfenninger, A. Synthesis 1986, 89.
14. (a) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982, 104, 1737–
1739; (b) Chakraborty, T. K.; Suresh, V. R. Tetrahedron Lett. 1998, 39, 7775–
7778.
1H NMR (200 MHz, CDCl3): d 7.71–7.59 (m, 4H), 7.48–7.21 (m, 11H), 4.47 (s,
2H), 3.76–3.56 (m, 2H), 3.54–3.43 (m, 1H), 3.39–3.28 (m, 1H), 3.26–3.14 (m,
1H), 2.15 (br s, 1H), 1.96–1.53 (m, 3H), 1.49–1.33 (m, 1H), 1.05 (s, 9H), 1.0–0.77
(m, 10H). 13C NMR (75 MHz, CDCl3): d 138.9, 135.9, 135.8, 133.5, 133.3, 130.0,
129.9, 128.5, 127.9, 127.7, 127.6, 96.3, 75.4, 73.3, 68.8, 37.9, 37.1, 33.7, 31.1,
27.1, 19.4, 19.1, 15.9, 11.1. MS (ESI): m/z 541.0 (M+Na)+. HRMS (ESI): calcd for
C33H46O3 Na Si: 541.3113. Found : 541.3100.
22. Analytical data for compound 7: Colorless oil; ½a D25
ꢁ
+17.7 (c 0.6, CHCl3). IR (KBr):
3441, 2958, 2928, 2859, 1724, 1466, 1428, 1382, 1108, 823, 740, 703 cmꢀ1
.
1H
NMR (300 MHz, CDCl3): d 7.67–7.59 (m, 4H), 7.43–7.30 (m, 6H), 3.81–3.71 (m,
1H), 3.55–3.43 (m, 2H), 3.33–3.42 (m, 1H), 2.89–2.83 (m, 1H), 2.62–2.53 (m,
1H), 1.78–1.62 (m, 1H), 1.58–1.39 (m, 4H), 1.38–1.22 (m, 3H), 1.05 (s, 9H), 0.98
(d, J = 6.6 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H), 0.83 (d, J = 6.4 Hz, 3H). 13C NMR
(75 MHz, CDCl3): d 135.5, 134.0, 129.5, 127.5, 68.8, 61.8, 60.6, 58.4, 41.3, 41.3,
33.1, 32.7, 27.6, 26.8, 20.7, 19.2, 18.0, 17.7. MS (ESI): m/z 477.0 (M+Na)+. HRMS
(ESI): calcd for C28H42O3NaSi: 477.2800. Found: 477.2819.
23. Analytical data for compound 6: Colorless liquid; ½a D25
ꢀ21.0 (c 2.4, CHCl3). IR
ꢁ
(KBr): 3417, 2954, 2927, 2856, 1720, 1460, 1373, 1252, 1080, 1042, 835, 773,
736 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.42–7.25 (m, 5H), 4.49 (ABq, J = 11.8,
.
17.7 Hz, 2H), 3.73–3.65 (m, 1H), 3.60–3.43 (m, 3H), 3.33 (dd, J = 6.9, 10.5 Hz,
1H), 1.82–1.48 (m, 5H), 1.47–1.21 (m, 2H), 0.98–0.77 (m, 20H), 0.04 (s, 3H),
0.03 (s, 3H). 13C NMR (75 MHz, CDCl3): d 138.5, 134.8, 129.6, 128.3, 127.6,
127.4, 72.9, 67.8, 67.6, 40.9, 40.2, 35.6, 33.3, 33.1, 29.7, 28.0, 26.5, 25.9, 21.3,
18.1, 15.5, -4.25, -4.44. MS (ESI): m/z 445.0 (M+Na)+. HRMS (ESI) : calcd for
C25H46O3NaSi: 445.3113. Found: 445.3103.
24. Analytical data for compound 18: Viscous liquid; ½a D25
ꢀ21.1 (c 1.0, CHCl3). IR
ꢁ
(KBr): 3447, 2956, 2923, 2853, 1720, 1649, 1461, 1368, 1254, 1217, 1091, 1042,
835, 771 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.39–7.24 (m, 5H), 6.76 (dd,
.
J = 8.6, 15.6 Hz, 1H), 5.78 (d, J = 15.4 Hz, 1H), 4.48 (ABq, J = 11.8, 17.7 Hz, 2H),
4.18 (q, J = 7.1, 14.3 Hz, 2H), 3.73–3.63 (m, 1H), 3.55–3.44 (m, 2H), 2.51–2.33

J. S. Yadav et al. / Tetrahedron Letters 50 (2009) 3772–3775
3775
(m, 1H), 1.80–1.53 (m, 4H), 1.50–1.32 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H), 1.03 (d,
J = 6.6 Hz, 3H), 0.97–0.82 (m, 14H), 0.78 (d, J = 6.7 Hz, 3H), 0.02 (s, 3H), 0.01 (s,
3H). 13C NMR (75 MHz, CDCl3): d 166.7, 154.3, 138.5, 128.3, 127.6, 127.4, 119.9,
72.9, 72.6, 67.5, 60.1, 43.3, 40.1, 35.3, 34.3, 32.2, 29.6, 27.9, 25.9, 20.9, 20.3,
18.0, 15.2, 14.2, ꢀ4.30, ꢀ4.49. MS (ESI): m/z 491.1 (M+H)+. HRMS (ESI): calcd
for C29H50O4NaSi: 513.3376. Found: 513.3397.
37.8, 35.4, 33.3, 29.6, 27.6, 26.3, 25.9, 20.9, 20.4, 18.1, 16.5, 15.4, ꢀ4.25,
ꢀ4.45. MS (ESI): m/z 660.0 (M+Na)+. HRMS (ESI): calcd for C38H59NNaO5Si:
660.4055. Found: 660.4066.
26. Analytical data for compound 3: Colorless oil; ½a D25
ꢀ29.1 (c 0.6, CHCl3). IR
ꢁ
(KBr): 2954, 2926, 2855, 1738, 1711, 1462, 1379, 1254, 1077, 1032, 835,
775 cmꢀ1 1H NMR (300 MHz, CDCl3): d 4.58 (m, 1H), 4.04 (m, 1H), 3.86 (m,
.
25. Analytical data for compound 5: Colorless liquid; ½a D25
ꢁ
+9.3 (c 1.7, CHCl3). IR
(KBr): 3448, 2956, 2925, 2854, 1782, 1636, 1457, 1383, 1212, 1099, 835,
1H), 3.51 (m, 2H), 3.16 (m, 1H), 2.46 (d, J = 6.04 Hz, 2H), 1.89–1.33 (m, 11H),
0.95–0.78 (m, 26H), 0.07 (s, 3H), 0.05 (s, 3H). 13C NMR (75 MHz, CDCl3): d
176.3, 99.1, 98.6, 74.0, 73.7, 72.8, 62.2, 62.0, 45.6, 40.7, 40.2, 39.0, 35.9, 30.9,
30.8, 30.7, 27.5, 27.3, 27.2, 25.8, 25.5, 21.0, 20.9, 20.7, 19.6, 19.4, 18.0, 16.7,
16.6, 15.2, ꢀ4.5, ꢀ4.6. MS (ESI, nagative mode): m/z 471.1 (MꢀH)+; MS (ESI):
m/z 495.0 (M+Na)+. HRMS (ESI): calcd for C26H52NaO5Si: 495.3476. Found:
495.3486.
770 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.38–7.17 (m, 10H), 4.74–4.60 (m,
.
1H), 4.48 (ABq, J = 11.8, 17.3 Hz, 2H), 4.23–4.10 (m, 2H), 3.87–3.73 (m, 1H),
3.71–3.62 (m, 1H), 3.54–3.43 (m, 2H), 3.30–3.18 (m, 1H), 2.76 (dd, J = 9.6,
13.2 Hz, 1H), 1.80–1.43 (m, 6H), 1.38–1.14 (m, 8H), 0.96–0.76 (m, 18H), 0.02
(s, 3H), 0.01 (s, 3H). 13C NMR (75 MHz, CDCl3): d 177.7, 152.9, 138.5, 135.3,
129.4, 128.8, 128.2, 127.6, 127.4, 127.2, 72.9, 67.6, 65.9, 55.4, 45.1, 40.2, 39.4,